Novel antibacterial compounds, methods of making them, and uses thereof

ABSTRACT

The present invention relates to novel therapeutics with antibacterial activity, processes for their preparation, and pharmaceutical, veterinary and nutritional compositions containing them as active ingredients. The present invention also relates to uses of the novel therapeutics, for example, as medicants or food additives in the treatment of bacterial infections or to aid body mass gain in a subject.

This application is a continuation of U.S. patent application Ser. No.12/884,650, filed Sep. 17, 2010, which claims benefit of U.S.Provisional Patent Application Ser. No. 61/363,087, filed Jul. 9, 2010,which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel therapeutics which demonstrateantibacterial activity, processes for their preparation, pharmaceutical,veterinary, and nutritional compositions containing them as activeingredients, and their use, for example, as medicants or food additivesin the treatment of bacterial infections or to aid body mass gain in asubject.

BACKGROUND OF THE INVENTION

Natural products have been the single most productive source of leadsfor the development of drugs. Ninety five percent of the antibioticsdescribed to date originate from leads discovered by screening naturalproduct extracts or fractions. Many marketed antibacterial drugs aresemisynthetic congeners of natural products, and are obtained from thechemical refinement of fermentation products (e.g., oritavancin,tigecyclin, telithromycin, rifampicin). Although a robust pipeline ofnatural-product based antibiotics recently existed, an unrelentingantimicrobial resistance to these medicines has eroded the physician'sarsenal with which to treat infectious disease.

Over the past several decades, the frequency of antimicrobial resistanceand its association with serious infectious diseases has increased atalarming rates. The increasing resistance to the current arsenal ofantibiotics is of growing concern. A release by the National Instituteof Allergy and Infectious Diseases (April 2006) reported that:

-   -   Nearly two million patients in the United States get an        infection in the hospital each year. Of those patients, about        90,000 die each year as a result of their infection. This is up        from 13,300 patient deaths in 1992.    -   In 2003, epidemiologists reported in the New England Journal of        Medicine that 5 to 10 percent of patients admitted to hospitals        acquire an infection during their stay, and that the risk for a        hospital-acquired infection has risen steadily in recent        decades.    -   More than 70 percent of the bacteria that cause        hospital-acquired infections are resistant to at least one of        the drugs most commonly used to treat them.    -   Strains of S. aureus resistant to methicillin (MRSA) are endemic        in hospitals and are increasing in non-hospital settings such as        locker rooms.    -   A number of cases of community-associated MRSA have also been        reported, including cases in patients without established risk        factors.    -   The first S. aureus infections resistant to vancomycin (VRSA)        emerged in the United States in 2002.    -   Increasing reliance on vancomycin has led to the emergence of        vancomycin-resistant enterococci infections.

Now that vancomycin resistance has been established in S. aureus, it isexpected to increase at rates similar to those witnessed for vancomycinresistant enterococci, becoming endemic in United States hospitals by2015. To maintain our current level of therapeutic efficacy, newantibiotics, with new mechanisms of action and chemotypes need to bedeveloped.

The present invention is directed to overcoming these and otherdeficiencies in the prior art.

SUMMARY OF THE INVENTION

The present invention relates to a therapeutic having a structurecomprising formula I as follows:

wherein:the carbohydrate anomeric carbon designated * is in the R or Sconfiguration;R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl,heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³;R² is selected from the group consisting of H, —OR¹², —NR¹²R¹³,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamatemoiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to3 times with halogen, cyano, —NO₂, NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄haloalkyl, alkoxy, or an amino acid group;R³ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁴ is selected from the group consisting of H, halogen, —OR¹², C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴, ═NR¹⁴, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup;R⁶ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;or R⁵ and R⁶ can combine to form a heterocycle group containing from 1to 5 heteroatoms selected from the group consisting of oxygen, nitrogen,and sulfur and optionally substituted 1 to 3 times with halogen, oxo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁸ and R⁹ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, and a carbonate moiety, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl,and benzyl is optionally substituted from 1 to 3 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and an amino acid group;or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an ═NR¹⁴moiety;R¹⁰ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein eachof —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, and benzyl is optionally substituted 1 to 3 times withhalogen, cyano, —NO₂, —NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, or an amino acid group;R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group;R¹² and R¹³ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH;or R¹² and R¹³ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;R¹⁴ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,—(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group;R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄ haloalkyl, orphenyl, wherein each of C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄haloalkyl, and phenyl is optionally substituted 1 to 3 times withhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;R¹⁶ and R¹⁷ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵,—C(O)OR¹⁵, phenyl, or benzyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionallysubstituted from 1 to 3 times with a substituent selected independentlyat each occurrence thereof from the group consisting of halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an amino acid group;or R¹⁶ and R¹⁷ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;

X is O or N; Y is O or N;

m is 0, 1, 2, or 3;n is 0 to 5;q is 0, 1, or 2; and

represents an optional double bond;with the provisos: (1) if R¹ is H, R² is OCH₃, R³ is H, R⁴ is OH, R⁵ isH, R⁷ is H, R⁸ and R⁹ are combined to form an oxo, R¹⁰ is H, and X and Yare O, then at least one of R¹ to R¹⁰ is a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, or a carbonate moiety; and (2) thatX, R⁶, R⁸, and R⁹ can form a dihydroquinone ring;or an oxide thereof, a pharmaceutically acceptable salt thereof, or asolvate thereof.

Another aspect of the present invention relates to a therapeutic havinga structure comprising formula I as follows:

wherein:the carbohydrate anomeric carbon designated * is in the R or Sconfiguration;R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl,heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³;R² is selected from the group consisting of H, —OR¹², —NR¹²R¹³,—(CH₂)_(n)C(O)R¹¹, alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3times with halogen, cyano, —NO₂, —NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄haloalkyl, alkoxy, or an amino acid group;R³ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or N¹²R¹³;R⁴ is selected from the group consisting of H, halogen, —OR¹², C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴, ═NR¹⁴, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup;R⁶ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;or R⁵ and R⁶ can combine to form a heterocycle group containing from 1to 5 heteroatoms selected from the group consisting of oxygen, nitrogen,and sulfur and optionally substituted 1 to 3 times with halogen, oxo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁸ and R⁹ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, and a carbonate moiety, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl,and benzyl is optionally substituted from 1 to 3 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and an amino acid group;or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an ═NR¹⁴moiety;R¹⁰ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein eachof —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, and benzyl is optionally substituted 1 to 3 times withhalogen, cyano, —NO₂, —NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, or an amino acid group; or R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, and R¹⁰ are each, independently, an O-glycosidic bond, anN-glycosidic bond, a C-glycosidic bond, or a peptide bond;R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group;R¹² and R¹³ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH;or R¹² and R¹³ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;R¹⁴ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,—(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, NO₂, —OR¹², —NR¹²R¹³, or anamino acid group;R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄ haloalkyl, orphenyl, wherein each of C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄haloalkyl, and phenyl is optionally substituted 1 to 3 times withhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;R¹⁶ and R¹⁷ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵,—C(O)OR¹⁵, phenyl, or benzyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionallysubstituted from 1 to 3 times with a substituent selected independentlyat each occurrence thereof from the group consisting of halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an amino acid group;or R¹⁶ and R¹⁷ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;

X is O or N; Y is O or N;

m is 0, 1, 2, or 3;n is 0 to 5;q is 0, 1, or 2; and

represents an optional double bond;with the provisos: (1) if R¹ is H, R² is OCH₃, R³ is H, R⁴ is OH, R⁵ isH, R⁷ is H, R⁸ and R⁹ are combined to form an oxo, R¹⁰ is H, and X and Yare O, then at least one of R¹ to R¹⁰ is an O-glycosidic bond, anN-glycosidic bond, a C-glycosidic bond, or a peptide bond; and (2) thatX, R⁶, R⁸, and R⁹ can form a dihydroquinone ring;or an oxide thereof, a pharmaceutically acceptable salt thereof, or asolvate thereof.

The present invention also relates to pharmaceutical compositions,cosmetic compositions, veterninary compositions, methods of treating orpreventing a bacterial infection in a subject including administering atherapeutic having a structure comprising formula I to the subject, andmethods of enhancing growth in a subject including administering atherapeutic including a structure of formula I to the subject.

Yet another aspect of the present invention relates to a method formaking a product compound having the formula:

said method including fermenting a culture medium including Streptomycesstrain AMRI-7957 (ATCC Accession No. PTA-11098) under conditionseffective to produce a fermentation broth comprising the productcompound, and isolating the product compound.

A further aspect of the present invention relates to a Streptomycesstrain AMRI-7957 having ATCC Accession No. PTA-11098.

An additional aspect of the present invention relates to a method formaking a product compound having the formula:

said method including culturing a culture medium including Streptomycesstrain AMRI-45379 under conditions effective to produce a suspensioncomprising the product compound, and isolating the product compound.

A further aspect of the present invention relates to a Streptomycesstrain AMRI-45379 having ATCC Accession No. PTA-11097.

Yet another aspect of the present invention relates to methods of makingthe compounds of formula I of the present invention.

The continuing development of resistance to antibiotics, including thosemore recently introduced to the clinic (Seedat et al., “Rapid Emergenceof Resistance to Linezolid During Linezolid Therapy of an Enterococcusfaecium Infection,” Antimicrob. Agents Chemotherapy, 50(12):4217-4219(2006) and Hayden et al., “Development of Daptomycin Resistance In Vivoin Methicillin-Resistant Staphylococcus aureus,” J. Clin. Microbiol.,43(10):5285-5287 (2005), which are hereby incorporated by reference intheir entirety), necessitates the development of new antibiotics thatare able to overcome existing mechanisms of resistance for the treatmentof bacterial infection, including those associated with multi-drugresistance organisms. The present invention provides compounds which canbe used to treat multi-drug resistant strains.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a therapeutic having a structurecomprising formula I as follows:

wherein:the carbohydrate anomeric carbon designated * is in the R or Sconfiguration;R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl,heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³;R² is selected from the group consisting of H, —OR¹², —NR¹²R¹³,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamatemoiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to3 times with halogen, cyano, —NO₂, —NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄haloalkyl, alkoxy, or an amino acid group;R³ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁴ is selected from the group consisting of H, halogen, —OR¹², C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴, ═NR¹⁴, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup;R⁶ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;or R⁵ and R⁶ can combine to form a heterocycle group containing from 1to 5 heteroatoms selected from the group consisting of oxygen, nitrogen,and sulfur and optionally substituted 1 to 3 times with halogen, oxo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁸ and R⁹ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, and a carbonate moiety, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl,and benzyl is optionally substituted from 1 to 3 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and an amino acid group;or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an ═NR¹⁴moiety;R¹⁰ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein eachof —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, and benzyl is optionally substituted 1 to 3 times withhalogen, cyano, —NO₂, NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, or an amino acid group;R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group;R¹² and R¹³ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH;or R¹² and R¹³ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;R¹⁴ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,—(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group;R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄ haloalkyl, orphenyl, wherein each of C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄haloalkyl, and phenyl is optionally substituted 1 to 3 times withhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;R¹⁶ and R¹⁷ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵,—C(O)OR¹⁵, phenyl, or benzyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionallysubstituted from 1 to 3 times with a substituent selected independentlyat each occurrence thereof from the group consisting of halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an amino acid group;or R¹⁶ and R¹⁷ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;

X is O or N; Y is O or N;

m is 0, 1, 2, or 3;n is 0 to 5;q is 0, 1, or 2; and

represents an optional double bond;with the provisos: (1) if R¹ is H, R² is OCH₃, R³ is H, R⁴ is OH, R⁵ isH, R⁷ is H, R⁸ and R⁹ are combined to form an oxo, R¹⁰ is H, and X and Yare O, then at least one of R¹ to R¹⁰ is a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, or a carbonate moiety; and (2) thatX, R⁶, R⁸, and R⁹ can form a dihydroquinone ring;or an oxide thereof, a pharmaceutically acceptable salt thereof, or asolvate thereof.

Another aspect of the present invention relates to a therapeutic havinga structure comprising formula I as follows:

wherein:the carbohydrate anomeric carbon designated * is in the R or Sconfiguration;R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl,heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³;R² is selected from the group consisting of H, —OR¹², —NR¹²R¹³,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamatemoiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to3 times with halogen, cyano, —NO₂, NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄haloalkyl, alkoxy, or an amino acid group;R³ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or N¹²R¹³;R⁴ is selected from the group consisting of H, halogen, —OR¹², C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴, ═NR¹⁴, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁵ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup;R⁶ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;or R⁵ and R⁶ can combine to form a heterocycle group containing from 1to 5 heteroatoms selected from the group consisting of oxygen, nitrogen,and sulfur and optionally substituted 1 to 3 times with halogen, oxo,cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³;R⁸ and R⁹ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, and a carbonate moiety, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl,and benzyl is optionally substituted from 1 to 3 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and an amino acid group;or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an ═NR¹⁴moiety;R¹⁰ is optionally present and, if present, is selected from the groupconsisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆alkyl, C₁-C₆ haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, acarbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety, wherein eachof —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆haloalkyl, and benzyl is optionally substituted 1 to 3 times withhalogen, cyano, —NO₂, —NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, or an amino acid group;or R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each, independently,an O-glycosidic bond, an N-glycosidic bond, a C-glycosidic bond, or apeptide bond;R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group;R¹² and R¹³ are each independently selected from the group consisting ofH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH;or R¹² and R¹³ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;R¹⁴ is selected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, (CH₂)_(n)OC(O)NR¹²R¹³,—(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group;R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄ haloalkyl, orphenyl, wherein each of C₁-C₄ alkyl, arylalkyl, heteroarylalkyl C₁-C₄haloalkyl, and phenyl is optionally substituted 1 to 3 times withhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group;R¹⁶ and R¹⁷ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵,—C(O)OR¹⁵, phenyl, or benzyl, wherein each of C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl is optionallysubstituted from 1 to 3 times with a substituent selected independentlyat each occurrence thereof from the group consisting of halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an amino acid group;or R¹⁶ and R¹⁷ are taken together with the nitrogen to which they areattached to form a five- to seven-membered heterocyclic ring, which maybe saturated or unsaturated and comprises from 1 to 2 heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andis optionally substituted from 1 to 4 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;

X is O or N; Y is O or N;

m is 0, 1, 2, or 3;n is 0 to 5;q is 0, 1, or 2; and

represents an optional double bond;with the provisos: (1) if R¹ is H, R² is OCH₃, R³ is H, R⁴ is OH, R⁵ isH, R⁷ is H, R⁸ and R⁹ are combined to form an oxo, R¹⁰ is H, and X and Yare O, then at least one of R¹ to R¹⁰ is an O-glycosidic bond, anN-glycosidic bond, a C-glycosidic bond, or a peptide bond; and (2) thatX, R⁶, R⁸, and R⁹ can form a dihydroquinone ring;or an oxide thereof, a pharmaceutically acceptable salt thereof, or asolvate thereof.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings. If not defined otherwise herein, all technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. In the event that there is a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

The term “alkyl” means an aliphatic hydrocarbon group which may bestraight or branched. When not otherwise restricted, the term refers toan alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groupshaving about 1 to about 6 carbon atoms in the chain. Branched means thatone or more lower alkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. Exemplary alkyl groups include methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and thelike.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. In the present invention, the term“alkenyl” may also refer to a hydrocarbon chain having 2 to 6 carbonscontaining at least one double bond and at least one triple bond.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl.

The term “alkoxy” means groups of from 1 to 8 carbon atoms of astraight, branched, or cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, andthe like. Lower-alkoxy refers to groups containing one to four carbons.For the purposes of the present patent application, alkoxy also includesmethylenedioxy and ethylenedioxy in which each oxygen atom is bonded tothe atom, chain, or ring from which the methylenedioxy or ethylenedioxygroup is pendant so as to form a ring. Thus, for example, phenylsubstituted by alkoxy may be, for example,

or

The term “alkoxyalkyl” means an alkyl residue attached to an alkoxygroup, as herein described.

The term “amino acid group” means a side chain including an alpha-aminoacid with the general formula H₂NCHRCOOH, where R is an organicsubstituent.

The term “aryl” means an aromatic monocyclic or multi-cyclic(polycyclic) ring system of 6 to about 19 carbon atoms, preferably of 6to about 10 carbon atoms, and includes arylalkyl groups. The ring systemof the aryl group may be optionally substituted. Representative arylgroups of the present invention include, but are not limited to, groupssuch as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl,fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

The term “arylalkyl” means an alkyl residue attached to an aryl ring.Examples are benzyl, phenethyl, and the like. Attachment can be throughthe alkyl or aryl residue.

The term “benzyl ether moiety” means a pendant group within the compoundof formula I which includes a benzyl ether group. The benzyl ether groupmay be present within the benzyl ether moiety as a terminal group or asa non-terminal group. Other moieties and functional groups may bepresent in the benzyl ether moiety provided that the descriptive moietyis still present.

The term “carbamate moiety” means a pendant group within the compound offormula I which includes a carbamate group. The carbamate group may bepresent within the carbamate moiety as a terminal group or as anon-terminal group. Other moieties and functional groups may be presentin the carbamate moiety provided that the descriptive moiety is stillpresent.

The term “carbonate moiety” means a pendant group within the compound offormula I which includes a carbonate group. The carbonate group may bepresent within the carbonate moiety as a terminal group or as anon-terminal group. Other moieties and functional groups may be presentin the carbonate moiety provided that the descriptive moiety is stillpresent.

The term “compounds of the invention”, and equivalent expressions, aremeant to embrace compounds of general formula I as hereinbeforedescribed, which expression includes the prodrugs, the pharmaceuticallyacceptable salts, the oxides, the solvates, e.g. hydrates, and inclusioncomplexes of that compound, where the context so permits, as well as anystereoisomeric form, or a mixture of any such forms of that compound inany ratio. Inclusion complexes are described in Remington, The Scienceand Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is herebyincorporated by reference in its entirety. The most commonly employedinclusion complexes are those with cyclodextrins, and all cyclodextrincomplexes, natural and synthetic, are specifically encompassed withinthe claims. Thus, in accordance with some embodiments of the invention,a compound as described herein, including in the contexts ofpharmaceutical compositions, methods of treatment, and compounds per se,is provided as the salt form. Similarly, reference to intermediates,whether or not they themselves are claimed, is meant to embrace theirsalts, and solvates, where the context so permits. For the sake ofclarity, particular instances when the context so permits are sometimesindicated in the text, but these instances are purely illustrative andit is not intended to exclude other instances when the context sopermits.

The term “cycloalkyl” means a non-aromatic, saturated or unsaturated,mono or multi-cyclic ring system of about 3 to about 7 carbon atoms,preferably of about 5 to about 7 carbon atoms, and which may include atleast one double bond. Exemplary cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclophenyl,anti-bicyclopropane, and syn-tricyclopropane.

The term “cycloalkylalkyl” means an cycloalkyl-alkyl-group in which thecycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkylgroups include cyclopropylmethyl and cyclopentylmethyl. The alkylradical and the cycloalkyl radical may be optionally substituted asdefined herein.

The term “functional group” means a specific atom or group of atomswithin a molecule that is responsible for the characteristic chemicalreactions of those molecules. The same functional group will undergo thesame or similar chemical reaction(s) regardless of the size of themolecule it is a part of. However, its relative reactivity can bemodified by nearby functional groups.

The term “haloalkyl” means both branched and straight-chain alkylsubstituted with one or more halogen, wherein the alkyl group is asherein described.

The term “halogen” means fluorine, chlorine, bromine, or iodine.

The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ringsystem of about 5 to about 19 ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example, nitrogen, oxygen, or sulfur.In the case of multi-cyclic ring system, only one of the rings needs tobe aromatic for the ring system to be defined as “heteroaryl”. Preferredheteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia,or thio before heteroaryl means that at least a nitrogen, oxygen, orsulfur atom, respectively, is present as a ring atom. A nitrogen,carbon, or sulfur atom in the heteroaryl ring may be optionallyoxidized; the nitrogen may optionally be quaternized. Representativeheteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(311)-yl, and the like.

The term “heteroarylalkyl” means an alkyl residue attached to aheteroaryl ring. Examples are 3-picolyl, 1-(furan-2-yl)propan-2-ol, andthe like.

As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to18-membered ring (radical) which consists of carbon atoms and from oneto five heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this invention, the heterocycle maybe a monocyclic, or a polycyclic ring system, which may include fused,bridged, or spiro ring systems; and the nitrogen, carbon, or sulfuratoms in the heterocycle may be optionally oxidized; the nitrogen atommay be optionally quaternized; and the ring may be partially or fullysaturated. Examples of such heterocycles include, without limitation,azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl,tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, 2-oxooxazolidinyl,3-oxomorpholino, 1,1-dioxothiomorpholino, tetrohydro-2H-oxazinyl,oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl,pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.Further heterocycles and heteroaryls are described in Katritzky et al.,eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions,Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press,N.Y. (1984), which is hereby incorporated by reference in its entirety.

The term “hydrogen” means all isotopes, including protium, deuterium,and tritium.

The term “method of treating” means amelioration or relief from thesymptoms and/or effects associated with the disorders described herein.

The term “monocyclic” used herein indicates a molecular structure havingone ring.

The term “multiple drug resistance” or “multi-drug resistance” usedherein indicates a condition enabling a disease-causing organism toresist distinct drugs or chemicals of a wide variety (National Libraryof Medicine Medica Subject Headings 2009,http:www.nim.nih.govcgiinesh2009 MB_cgi′?mode:::&tem=DRUG+RESISTANCE,+MULTIPLE,+BACTERIAL, which is hereby incorporated by reference in itsentirety). In clinical practice, an organism is considered multi-drugresistant when it is able to resist the activities of two or moredistinct varieties of structure that are effective against non-resistantstrains. For example, multi-drug resistant Tuberculosis is defined asresistant to isoniazid and rifampicin whether there is resistance toother drugs or not (Davies, Multi-Drug Resistant Tuberculosis,http:priory.comcmolTBMultid.htm, which is hereby incorporated byreference in its entirety). Microorganisms that can display multi-drugresistance include pathological bacteria and fungi. Microorganismsdevelop resistance to antimicrobial agents via spontaneous mutation andDNA transfer (Walsh, “Antibiotics. Actions, Origins, Resistance,”American Society for Microbiology (2003) and Bennett, British Journal ofPharmacology, 153(Suppl. 1):5347-5357 (2008), which are herebyincorporated by reference in their entirety). These processes allowpathological bacteria to become resistant to antibiotics used in theclinic and community, rendering the antibiotics ineffective (Walsh,“Antibiotics. Actions, Origins, Resistance,” American Society forMicrobiology (2003), which is hereby incorporated by reference in itsentirety). Microorganisms employ several mechanisms in attainingmulti-drug resistance including: (1) enzymatic deactiviation ofantibiotics through destruction or modification; (2) replacement ormodification of the antibiotic target; (3) use of efflux pumps to keepintracellular antibiotic concentrations below lethal levels (Li et al.,“Efflux-mediated Drug Resistance in Bacteria: An Update,” Drug,69(12):1555-1623 (2009) which is hereby incorporated by reference in itsentirety); and (4) an increased mutation rate as a response to stress(Stix, “An Antibiotic Resistance Fighter,” Scientific American,294(4):81-83 (2006), which is hereby incorporated by reference in itsentirety). Many different bacteria now exhibit multi-drug resistance,including staphylococci, enterococci, gonococci, streptococci,salmonella, pseudomonas, Mycobacterium tuberculosis, and others. Inaddition, some resistant bacteria are able to transfer copies of DNAthat codes for a mechanism of resistance to other bacteria, therebyconferring resistance to their neighbors, which then are also able topass on the resistant gene (Bennett, British Journal of Pharmacology,153(Suppl. 1):S347-S357 (2008), which is hereby incorporated byreference in its entirety).

The term “═NR¹⁴ moiety” means a pendant group within the compound offormula I which includes an ═NR¹⁴ group. The ═NR¹⁴ group may be presentwithin the ═NR¹⁴ moiety as a terminal group or as a non-terminal group.Other moieties and functional groups may be present in the ═NR¹⁴ moietyprovided that the descriptive moiety is still present. Suitable═NR¹⁴moieties include, but are not limited to, hydrazone moieties and acylhydrazide moieties.

The term “pharmaceutical composition” means a composition comprising atherapeutic including a structure of formula I and at least onecomponent comprising pharmaceutically acceptable carriers, diluents,adjuvants, excipients, or vehicles, such as preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavoring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispensing agents, depending on the nature of the mode of administrationand dosage forms. As used herein, the term “pharmaceutically acceptablecarrier” is used to mean any carrier, diluent, adjuvant, excipient, orvehicle, as described herein. Examples of suspending agents includeethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agaragar and tragacanth, or mixtures of these substances. Variousantibacterial and antifungal agents can be included, for example,parabens, chlorobutanol, phenol, sorbic acid, and the like. It may alsobe desirable to include isotonic agents, for example sugars, sodiumchloride, and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monosterate and gelatin. Examples ofsuitable carriers, diluents, solvents, or vehicles include water,ethanol, polyols, suitable mixtures thereof, vegetable oils (such asolive oil), and injectable organic esters such as ethyl oleate. Examplesof excipients include lactose, milk sugar, sodium citrate, calciumcarbonate, and dicalcium phosphate. Examples of disintegrating agentsinclude starch, alginic acids, and certain complex silicates. Examplesof lubricants include magnesium stearate, sodium lauryl sulphate, talc,as well as high molecular weight polyethylene glycols.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgment, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable dosage forms” means dosage formsof the compound of the invention, and includes, for example, tablets,dragees, powders, elixirs, syrups, liquid preparations, includingsuspensions, sprays, inhalants tablets, lozenges, emulsions, solutions,granules, capsules, and suppositories, as well as liquid preparationsfor injections, including liposome preparations. Techniques andformulations generally may be found in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., latest edition, which ishereby incorporated by reference in its entirety.

The term “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in vivo to yield the parent compound of theabove formula, for example by hydrolysis in blood. Commonly, theconversion of prodrug to drug occurs by enzymatic processes in the liveror blood of the mammal Many of the compounds of the invention may bechemically modified without absorption into the systemic circulation,and in those cases, activation in vivo may come about by chemical action(as in the acid-catalyzed cleavage in the stomach) or through theintermediacy of enzymes and microflora in the gastrointestinal GI tract.Functional groups which may be rapidly transformed, by metaboliccleavage, in vivo form a class of groups reactive with the carboxylgroup of the compounds of this invention. They include, but are notlimited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl,and the like), unsubstituted and substituted aroyl (such as benzoyl andsubstituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formedwith dicarboxylic acids (such as succinyl), and the like. Because of theease with which the metabolically cleavable groups of the compoundsuseful according to this invention are cleaved in vivo, the compoundsbearing such groups act as pro-drugs. The compounds bearing themetabolically cleavable groups have the advantage that they may exhibitimproved bioavailability as a result of enhanced solubility and/or rateof absorption conferred upon the parent compound by virtue of thepresence of the metabolically cleavable group. A thorough discussion ofprodrugs is provided in the following: Design of Prodrugs, H. Bundgaard,ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed.,Academic Press, 42, p. 309-396 (1985); A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Designand Applications of Prodrugs,” p. 113-191 (1991); Advanced Drug DeliveryReviews, H. Bundgaard, 8, p. 1-38 (1992); Journal of PharmaceuticalSciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692(1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press (1987), which are incorporated herein by reference intheir entirety. Examples of prodrugs include, but are not limited to,acetate, formate, and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. Suitablepharmaceutically acceptable acid addition salts for the compounds of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Whenthe compounds contain an acidic side chain, suitable pharmaceuticallyacceptable base addition salts for the compounds of the presentinvention include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine.Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine, and tris (hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium,potassium, and sodium; alkali earth metal salts, such as but not limitedto barium, calcium, and magnesium; transition metal salts, such as butnot limited to zinc; and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl esters of acidicgroups, including, but not limited to, carboxylic acids, phosphoricacids, phosphinic acids, sulfonic acids, sulfinic acids, and boronicacids. Pharmaceutical acceptable enol ethers include, but are notlimited to, derivatives of formula C═C (OR) where R is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula C═C (OC(O) R) where R is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.Pharmaceutical acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

The term “polycyclic” or “multi-cyclic” used herein indicates amolecular structure having two or more rings, including, but not limitedto, fused, bridged, or spiro rings.

Terminology related to “protecting,” “deprotecting,” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups.” Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1991), which is hereby incorporated by reference in its entirety.

The term “substituted” or “substitution” of an atom means that one ormore hydrogen on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded.

The term “optionally substituted” is used to indicate that a group mayhave a substituent at each substitutable atom of the group (includingmore than one substituent on a single atom), provided that thedesignated atom's normal valency is not exceeded and the identity ofeach substituent is independent of the others. In accordance with thepresent invention, up to three H atoms in each residue are replaced withalkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy(also referred to as alkoxycarbonyl), carboxamido (also referred to asalkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atomsdictated by their valency. When a substituent is keto (i.e., =0), thentwo hydrogens on the atom are replaced. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds; by “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “solvate” refers to a compound of formula I in the solid state,wherein molecules of a suitable solvent are incorporated in the crystallattice. A suitable solvent for therapeutic administration isphysiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions.

The term “therapeutically effective amount” is meant to describe anamount of compound of the present invention effective in producing thedesired therapeutic effect. Such amounts generally vary according to anumber of factors well within the purview of ordinarily skilled artisansgiven the description provided herein to determine and account for.These include, without limitation: the particular subject, as well asits age, weight, height, general physical condition, and medicalhistory, the particular compound used, as well as the carrier in whichit is formulated and the route of administration selected for it; and,the nature and severity of the condition being treated.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Each chiral center may be defined, in terms ofabsolute stereochemistry, as (R)— or (S)—. The present invention ismeant to include all such possible isomers, as well as mixtures thereof,including racemic and optically pure forms. Optically active (R)— and(S)—, (−)- and (+)-, or (D)- and (L)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

This invention also envisions the “quaternization” of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

In the characterization of some of the substituents, it is recited thatcertain substituents may combine to form rings. Unless stated otherwise,it is intended that such rings may exhibit various degrees ofunsaturation (from fully saturated to fully unsaturated), may includeheteroatoms and may be substituted with lower alkyl or alkoxy.

In accordance with one embodiment of the present invention, R¹ isselected from the group consisting of H, C₁-C₆ alkyl,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, arylalkyl, andheteroarylalkyl, wherein n is 1.

In accordance with another embodiment of the present invention, R² is—OR¹⁴ or —NR¹²R¹³.

In accordance with another embodiment of the present invention, R³ isselected from the group consisting of H, halogen, —NR¹²R¹³, and —NO₂.

In accordance with another embodiment of the present invention, R⁴ isOH.

In accordance with another embodiment of the present invention, R⁴ is═NOH.

In accordance with another embodiment of the present invention, R⁵ is Hor C₁-C₆ alkyl.

In accordance with another embodiment of the present invention, R⁶ isselected from the group consisting of H, —OR¹², and —(CH₂)_(n)(O)R¹¹.

In accordance with another embodiment of the present invention, R⁷ is Hor halogen.

In accordance with another embodiment of the present invention, R⁸ isC₁-C₆ alkyl or phenyl, wherein phenyl is optionally substituted from 1to 3 times with halogen.

In accordance with another embodiment of the present invention, R⁹ isOH.

In accordance with another embodiment of the present invention, R⁸ andR⁹ are combined to form an oxo group.

In accordance with another embodiment of the present invention, R¹⁰ is Hor —OR¹².

In accordance with another embodiment of the present invention, X is O.

In accordance with another embodiment of the present invention, X is N.

In accordance with another embodiment of the present invention, Y is O.

In accordance with another embodiment of the present invention, Y is N.

In accordance with another embodiment of the present invention, X is N,R⁶ is —NR¹²R¹³, and R¹² is H.

In accordance with another embodiment of the present invention, X, R⁶,R⁸, and R⁹ form a dihydroquinone ring, as follows:

In accordance with another embodiment of the present invention, at leastone of R¹ to R¹⁰ is a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, or a carbonate moiety within the compound of formula I. Anexample of a compound of formula I including a benzyl ether moiety is(6R,6aS,14aR)-methyl1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(see Example 7). An example of a compound of formula I including acarbamate moiety is (6R,6aS,14aR)-methyl1,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-6-(methylcarbamoyloxy)-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate.An example of a compound of formula I including a carbonate moiety is(6R,6aS,14aR)-methyl1,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-6-(methoxycarbonyloxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate.An example of a compound of formula I including an ═NR¹⁴ moiety, whereinthe ═NR¹⁴ moiety is a hydrazone moiety is (6R,6aS,14aR)-methyl11-((2S,3R,5R,6S,Z)-3,5-dimethoxy-6-methyl-4-(2-propylhydrazono)tetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate.An example of a compound of formula I including an ═NR¹⁴ moiety, whereinthe ═NR¹⁴ moiety is an acyl hydrazide moiety is (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,12,14-trioxo-9-(2-propionylhydrazono)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate.

Exemplary compounds of the present invention including benzyl ethermoieties further include, but are not limited to:

where R is defined as any of R¹ to R¹⁷.

Additional exemplary compounds of the present invention includingcarbamate moieties further include, but are not limited to:

where R′ and R″ are defined as any of R¹ to R¹⁷.

Additional exemplary compounds of the present invention includingcarbonate moieties further include, but are not limited to:

Further exemplary compounds of the present invention including ═NR¹⁴moieties include, but are not limited to:

“Moieties” described herein (e.g., benzyl ether moiety, carbamatemoiety, carbonate moiety, or ═NR¹⁴ moiety) may be prepared directly bytransforming (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateor (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2R,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateor by reaction of derivatives to yield a new product with a covalentattachment. Subsequent transformation of such moiety is intended to beinclusive in the definition of moiety provided that the descriptivemoiety is still present in the product. An example of preparation of acompound of formula I including a benzyl ether moiety is shown below:

Either primary transformation or secondary transformation of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateresults in a “benzyl ether moiety”. (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatedoes not bear a benzyl ether attachment at any of the specifiedpositions and is therefore not a benzyl ether moiety.

Specific compounds of the present invention include, but are not limitedto:

-   (6R,6aS,14aR)-Methyl    6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a-dimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    6,14a-dihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a,8-trimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-1-(2-methoxy-2-oxoethoxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   2-((6R,6aS,14aR)-6,8,14a-Trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-1-yloxy)acetic    acid;-   (6R,6aS,14aR)-Methyl    1-(2-amino-2-oxoethoxy)-6,8,14a-trihydroxy-11-((3R,4R,5R,6S)-4-hydro    xy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(pyridin-3-ylmethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate    hydrochloride;-   (6R,6aS,14aR)-Methyl    6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic    acid;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(4-phenylpiperazine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone    hydrochloride;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-ylmethyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide    hydrochloride;-   (6R,6aS,14aR)—N-Cyclohexyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(piperidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone;-   (6R,6aS,14aR)—N-(Biphenyl-4-yl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-(2-hydroxyethyl)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(3-phenylpropyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)—N-(4-Fluorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)—N-(4-Chlorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N-(4-methoxybenzyl)-3-methyl-7,9-12-14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide    Hydrochloride;-   (6R,6aS,14aR)—N-Benzyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-isopropyl-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   Benzyl    246R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamido)acetate;-   (6R,6aS,14aR)-3-Phenylpropyl    1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Ethyl    1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-2-Morpholinoethyl    1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Isobutyl    1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide;-   (6R,6aS,14aR)-Benzyl    1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    11-((2S,3R,4R,5S,6S)-3,5-dimethoxy-6-methyl-4-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    4-bromo-1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    4,10-dibromo-1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    10-chloro-1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6S,6aS,14aR)-Methyl    4,10-dichloro-1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    4-amino-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate    2,2,2-trifluoroacetate;-   (6R,6aS,14aR)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR,E)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-9-(methylimino)-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR,E)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(hydroxyimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR,E)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(2-methoxyethylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR,E)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(3-methoxypropylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR,E)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(3-hydroxypropylimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1,6,8,14a-tetrahydroxy-11-(4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    11-(Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   2-{(Z)-3,5-Dimethoxy-2-methyl-6-[(6R,6 aS,14    aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino]-2H-pyran-4(3H,5H,6H)-ylideneaminooxy}acetic    acid;-   (6R,6aS,14aR)-Methyl 11-[(Z)-4-(2-amino    ethoxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino]-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1,8,14a-trihydroxy-6-(hydroxyimino)-11-[(Z)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino]-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3,12-dimethyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-12-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydro    xy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;-   (6R,6aS,14aR)-Methyl    12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate;    and-   (6R,6aS,14aR)-Methyl    1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12-((5-(2-hydroxypropyl)furan-3-yl)methyl)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate.

One embodiment of the present invention relates to pharmaceuticallyacceptable salts, or non-salt forms, of any of the compounds of formulaI described herein. In one embodiment, the salt is a HCl salt.

Single enantiomers, any mixture of enantiomers, including racemicmixtures, or diastereomers (both separated and as any mixtures) of thecompounds of the present invention are also included within the scope ofthe invention.

The scope of the present invention also encompasses active metabolitesof the present compounds.

The present invention also includes compounds of formula I, wherein oneor more of the atoms, e.g., C or H, are replaced by the correspondingradioactive isotopes of that atom (e.g., C replaced by ¹⁴C and Hreplaced by ³H), or a stable isotope of that atom (e.g., C replaced by¹³C or H replaced by ²H). Radioisotopes of hydrogen, carbon,phosphorous, fluorine, iodine and chlorine include ³H, ¹⁴C, ³⁵S, ¹⁸F,³²P ³³P ¹²⁵I, and ³⁶Cl, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Radiolabeled compounds described herein andprodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent. Such compounds have a variety of potentialuses, e.g., as standards and reagents in determining the ability of apotential pharmaceutical to bind to neurotransmitter proteins. Inaddition, in the case of stable isotopes, such compounds may have thepotential to favorably modify the biological properties, e.g.,pharmacological and/or pharmacokinetic properties, of compound offormula I. The details concerning selection of suitable sites forincorporating radioactive isotopes into the compounds are known to thoseskilled in the art.

Therapeutics of the present invention as described herein are useful asantibacterials, which includes activity against multi-drug resistantstrains. It may be found upon examination that compounds that are notpresently excluded from the claims are not patentable to the inventorsin this application. In that case, the exclusion of species and generain applicants' claims are to be considered artifacts of patentprosecution and not reflective of the inventors' concept or descriptionof their invention. The invention, in a compound aspect, is alltherapeutics including structures of formula I, except those that are inthe public's possession.

While it may be possible for compounds of formula I to be administeredas the raw chemical, it will often be preferable to present them as partof a pharmaceutical composition. Accordingly, another aspect of thepresent invention is a pharmaceutical composition containing atherapeutically effective amount of a therapeutic including a structureof formula I, or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable carrier. The carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Furthermore, when reference is made in an independent claim to acompound or a pharmaceutically acceptable salt thereof, it will beunderstood that claims which depend from that independent claim whichrefer to such a compound also include pharmaceutically acceptable saltsof the compound, even if explicit reference is not made to the salts.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents, orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

In one embodiment of the present invention, the pharmaceuticalcomposition further comprises one or more other therapeutic adjuncts,e.g., other compounds effective in treating bacterial infections orenhancing growth (body mass), that are known to persons of skill in theart. Such other therapeutic adjuncts are described below.

Another aspect of the present invention relates to a method of treatinga bacterial infection. This method involves selecting a subject with abacterial infection and administering to the subject a therapeuticallyeffective amount of a therapeutic including a structure of formula I.

Suitable subjects include, for example, fish, amphibians, reptiles,birds, and mammals. The term “mammal” is used in its dictionary sense.The term “mammal” includes, for example, mice, hamsters, rats, cows,sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris),cats, rabbits, guinea pigs, and primates, including humans.

Bacterial infections which are susceptible to treatment with atherapeutic in accordance with the present invention include Grampositive bacterial infections, Gram negative bacterial infections, andmulti-drug resistant bacterial infections (which may be Gram positive orGram negative). In particular, bacterial infections in accordance withthe present invention include, but are not limited to, epidermalinfection, acne, complicated skin and soft tissue bacterial infection,and bacterial pneumonia.

In one embodiment, the bacterial infection is a multi-drug resistantbacterial infection of a strain of Staphylococcus aureus, Streptococcuspneumoniae, or Enterococci.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of one or moretherapeutic adjuncts. Suitable therapeutic adjuncts include, but are notlimited to, antibiotic compounds, such as penicillins, cephalosporins,azetreonam, glycopeptides (e.g., vancomycin), bacitracin, carbacephem,carbapenems, aminoglycosides, tetracyclines, macrolides,chloramphenicol, clindamycin, quinolones, and sulfonamides.

The present invention also relates to a method of preventing a bacterialinfection in a subject. This method involves selecting a subjectsusceptible to bacterial infection and administering to the subject atherapeutic including a structure of formula I under conditionseffective to prevent a bacterial infection.

This method further involves administering an adjunct, if desired, asdescribed above.

Yet another aspect of the present invention relates to a method ofenhancing growth in a subject. This method involves selecting a subjectand administering to the subject a therapeutically effective amount of atherapeutic including a structure of formula I or a pharmaceuticallyacceptable salt thereof under conditions effective to enhance growth.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Yet another aspect of the present invention relates to a method formaking a product compound having the formula:

said method including fermenting a culture medium including Streptomycesstrain AMRI-7957 (ATCC Accession No. PTA-11098) under conditionseffective to produce a fermentation broth comprising the productcompound, and isolating the product compound.

Methods of fermenting are known in the art and are described in detailin the Examples below and include culturing a suspension including theproducing Streptomyces strain AMRI-7957 (ATCC Accession No. PTA-11098),and inoculating the culture into a fermentor.

Once the target compound has accumulated in the fermentor, it can beisolated. In accordance with the present invention, the product compoundcan be isolated from both the biomass fraction and the supernatantfraction of the fermentation broth. Accordingly, the biomass fractionand the supernatant fraction can be separated and the product compoundcan be extracted from each fraction.

A further aspect of the present invention relates to a Streptomycesstrain AMRI-7957 having ATCC Accession No. PTA-11098.

Yet another aspect of the present invention relates to a method ofmaking a product compound having the formula:

said method including culturing a culture medium including Streptomycesstrain AMRI-45379 under conditions effective to produce a suspensioncomprising the product compound, and isolating the product compound.

Suitable conditions for producing a suspending comprising the productcompound include microbial transformation techniques. Such microbialtransformation techniques include, for example, adding intermediate(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateto the culture medium and incubating under conditions effective to allowformation of the product compound (see, e.g., Example 62).

A further aspect of the present invention relates to a Streptomycesstrain AMRI-45379 having ATCC Accession No. PTA-11097.

Another aspect of the present invention relates to a method of making aproduct compound of formula I. This method involves treating a firstintermediate compound having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatewith R¹Z¹, wherein Z¹ is a halide and R¹ is as defined above.

A further aspect of the present invention relates to a method of makinga product compound of formula I which involves treating a firstintermediate compound having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatewith R²Z², wherein Z² is a halide or H and R² is as defined above.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate compound having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatecompound with N—R³-succinimide, wherein R³ is as defined above.

In another embodiment, wherein R³ is NO₂, treating comprises reactingthe first intermediate with a nitration agent. Suitable nitration agentsinclude, for example, zirconyl(IV) nitrate hydrate. In anotherembodiment, the method further includes reacting the compound of formulaI, wherein R³ is NO₂, with a reducing agent.

Yet another aspect of the present invention relates to a method ofmaking a product compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, wherein R⁴ is ═NR¹⁴, treating comprises reacting thefirst intermediate with NH₂R¹⁴.

A further aspect of the present invention relates to a method of makinga product compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatecompound with R⁵Z¹, wherein Z¹ is a halide and R⁵ is as defined above.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, wherein X is N, treating comprises reacting the firstintermediate with NH₂R⁶, wherein R⁶ is as defined above.

In another embodiment, the method further includes reacting the productcompound with a coupling agent such that R⁵ and R⁶ combine to form aheterocycle group containing from 1 to 5 heteroatoms selected from thegroup consisting of oxygen, nitrogen, and sulfur and optionallysubstituted 1 to 3 times with halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, or C₁-C₄ alkoxy.

Suitable coupling agents include, for example, carbonyldiimidazole.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatecompound with N—R⁷-succinimide, wherein R⁷ is as defined above.

In another embodiment, wherein R⁷ is NO₂, treating comprises reactingthe first intermediate with a nitration agent. Suitable nitration agentsinclude, for example, zirconyl(IV) nitrate hydrate. In anotherembodiment, the method further includes reacting the compound of formulaI, wherein R⁷ is NO₂, with a reducing agent.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatewith R⁸-M-L, wherein M is a metal and L is a halide. In anotherembodiment, treating comprises reacting the first intermediate withR⁹-M-L, wherein M is a metal and L is a halide.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, wherein Y is N, treating comprises reacting the firstintermediate with NH₂R¹⁰, wherein R¹⁰ is as defined above.

Another aspect of the present invention relates to a method of making aproduct compound of formula I which involves treating a firstintermediate having the structure:

under conditions effective to form the product compound.

In one embodiment, treating comprises reacting the first intermediatewith an imidate having a formula:

Suitable imidates include, but are not limited to,

Compounds according to the invention, for example, starting materials,intermediates, or products, are prepared as described herein or by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature.

Compounds useful according to the invention may be prepared by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature, for example, thosedescribed by Larock, Comprehensive Organic Transformations, Wiley-VCHpublishers, New York (1989), which is hereby incorporated by referencein its entirety.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio, orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice and as describedabove.

The novel compounds of formula I of this invention can be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents, and conventional synthesis procedures.Reagent 1 may be prepared by the methods described herein. In thesereactions, it is also possible to make use of variants that are known inthe art but are not mentioned here. Although the syntheses depictedherein may result in the preparation of enantiomers having a particularstereochemistry, included within the scope of the present invention arecompounds of formula I in any stereoisomeric form, and preparation ofcompounds of formula I in stereoisomeric forms other than those depictedherein would be obvious to one of ordinary skill in the chemical artsbased on the procedures presented herein.

The compounds of formula 2 may be prepared from a mixture of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate,potassium carbonate, and alkyl halide (R¹X). The reaction is carried outin a solvent, e.g., acetone, and heated under reflux until completion.Alternatively, the compounds of formula 2 may be prepared with themixture described above in DMF at room temperature until completion. Thecompletion is reached as shown by LC-MS or TLC analysis. The product 2may be purified by preparative TLC or preparative HPLC or normal phasechromatography.

Examples of compounds produced in accordance with Scheme 1 are shown inTable 1, below:

TABLE 1 Example # R¹X R¹ R⁵ Conditions 4 CH₃I CH₃ H A 5 CH₃I CH₃ CH₃ A 6

H A 7

H A 8

H A 10 BrCH₂CONH₂ CH₂CONH₂ H A 11

H B 12

H B

The compound of formula 2b may be prepared from a mixture of 2a and 10%PdC in THF or appropriate solvent stirred under hydrogen (1 atm) at roomtemperature. The reaction mixture is filtered and concentrated. Theresidue is purified by routine chromatography such as preparative TLC orpreparative HPLC or normal phase chromatography to produce the compoundof formula 2b.

The compounds of formula 3a may be prepared from a mixture of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatein DMSO and lithium chloride. The reaction mixture is irradiated withmicrowaves at elevated temperature (e.g. 120° C.). The crude material ispurified by routine chromatography such as preparative TLC orpreparative HPLC or normal phase chromatography to obtain the compoundsof formula 3a.

Polystyrene-carbodiimide (PS-carbodiimide), 1-hydroxybenzotriazolehydrate (HOBt hydrate), and R²H may be added to the compounds of formula3a in THF or appropriate solvent (e.g., methylene chloride). Thereaction mixture is stirred at room temperature or slightly heated(e.g., 40° C.) under nitrogen or argon. A catalytic amount of4-pyrrolidinopyridine may be added to the reaction mixture. Before thestep of adding PS-carbodiimide, HOBt hydrate and R²H, palladium oncarbon (e.g. 10% PdC) may be add to the compounds of formula 3a in THFand the reaction mixture is stirred at room temperature under hydrogenatmosphere. The crude material is purified by routine chromatographysuch as preparative TLC or preparative HPLC or normal phasechromatography to produce the compounds of formula 3b.

Alternatively, potassium carbonate, alkyl halide (e.g. R²X), and acatalytic amount of potassium iodide may be added to the compounds offormula 3a, and then the reaction heated (e.g. to 70° C.) undernitrogen. The reaction mixture may then be concentrated under reducedpressure and the crude product purified by routine chromatography suchas preparative TLC or preparative HPLC or normal phase chromatography.The resulting product may be lyophilized from acetonitrile and water toyield the compounds of formula 3c.

Examples of compounds produced in accordance with Scheme 3 are shown inTable 2, below:

TABLE 2 Example # R² Compound 3b 14

15

16 (CH₃)₂N 17

18

19 NHCH₃ 20 NH₂ 21

22

23

24 NH(CH₂)₂OH 25 NH(CH₂)₃Ph 26

27

28

29

30

31 NHCH(CH₃)₂ 32

34 OEt 35

36 OCH₂CH(CH₃)₂ 37

Compound 3c 33 O(CH₂)₃Ph

The compounds of formula 4a may be produced by mixing compound 1 inchloroform with N—X-succinimide (e.g. N-chlorosuccinimide), followed byR′—O—O—R″(e.g., benzoyl peroxide). The reaction mixture is heated (e.g.75° C.). The N—X-succinimide may then be re-charged and reaction mixtureheated again. After cooling to room temperature, the reaction mixture isdiluted with chloroform and washed with saturated sodium bicarbonate.The aqueous layer may be further extracted with chloroform. The combinedorganics are dried (Na₂SO₄), filtered, and concentrated. The crudematerial is purified by routine chromatography such as preparative TLCor preparative HPLC or normal phase chromatography to produce compoundsof formula 4a.

Examples of compounds produced in accordance with Scheme 4 are shown inTable 3, below:

TABLE 3 Example # R⁷ R³ 38 H Br 39 Br Br 40 Cl H 40 Cl Cl

The compound of formula 4b may be produced from a mixture of compound 1and zirconyl(IV) nitrate hydrate in an appropriate solvent (e.g.,acetonitrile). The reaction mixture is heated (e.g. to 70° C.) and,after cooling to room temperature, the reaction mixture is filtered andthe filtrate concentrated under reduced pressure. The crude material maybe purified by routine chromatography such as preparative TLC orpreparative HPLC or normal phase chromatography 4b.

Palladium on carbon (e.g. 10% PdC) may be added to a solution of 4b inethanol and THF and the reaction mixture shaked under a hydrogenatmosphere at 45 psi at ambient temperature. The reaction mixture may befiltered through diatomaceous earth and the filtrate concentrated underreduced pressure. The crude material may be purified by routinechromatography such as preparative TLC or preparative HPLC or normalphase chromatography to produce compound 4c.

To produce compounds 5, NH₂R⁶ may be added to a solution of compound 1in alcoholic solvent (e.g. methanol and/or pyridine) at roomtemperature, and the mixture stirred under inert atmosphere. Thereaction mixture may be quenched with a saturated solution of ammoniumchloride and extracted with chloroform. The extract may be washed (e.g.,with brine or 1N HCl and brine or water), dried, filtered, andconcentrated. The residue may be purified by routine chromatography suchas preparative TLC or preparative HPLC or normal phase chromatography toproduce the compounds of formula 5.

Examples of compounds produced in accordance with Scheme 6 are shown inTable 4, below:

TABLE 4 Example # R⁶ 43 H 45 OH 44 CH₃ 48 (CH₂)₃OH 46 (CH₂)₂OCH₃ 47(CH₂)₃OCH₃

The compounds of formula 7 may be produced from a mixture of compound 1in methylene chloride and Dess-Martin periodinane at room temperature,stirred under nitrogen atmosphere. The reaction mixture may be quenchedwith a saturated solution of sodium bicarbonate and extracted with ethylacetate. The combined extracts may be washed with brine, dried,filtered, and concentrated to afford a ketone (compound 7). NH₂R¹⁰ andpyridine is added to a solution of the compound 7 in methanol at roomtemperature. The mixture is stirred under nitrogen and the reactionmixture quenched with 1 N HCl and extracted with ethyl acetate. Thecombined extracts may be washed with brine, dried, filtered, andconcentrated. The residue may be purified by routine chromatography suchas preparative TLC or preparative HPLC or normal phase chromatography toproduce compounds of formula 8a.

Examples of compounds produced in accordance with Scheme 7 are shown inTable 5, below:

TABLE 5 Example # R¹⁰ R⁴ 49 OH (isomer A) OH 49 OH (isomer B) OH 50 OCH₃OH 51 OCH₂CO₂H OH 52 O(CH₂)₂NH₂ OH

In Scheme 8, a diketone (compound 7a) is produced following theprocedure of Scheme 7. NH₂R¹⁰ and pyridine is added to a solution ofcompound 7a in methanol at room temperature. The mixture is stirredunder nitrogen and the reaction mixture quenched with 1 N HCl andextracted with ethyl acetate. The combined extracts may be washed withbrine, dried, filtered, and concentrated. The residue may be purified bypreparative TLC to produce compound 8a.

In Scheme 9, a mixture of compound 1,(2R,3R,4S,5R)-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)-tetrahydro-2H-pyran-3,4,5-triyltriacetate, and 4 Å molecular sieves in dichloromethane is stirred atroom temperature under nitrogen. Then borontrifluoride diethyl etherateis added at 40° C. Upon completion (TLC analysis), the reaction isquenched with sodium bicarbonate, filtered through diatomaceous earth,and concentrated. The crude product may be purified by routinechromatography such as preparative TLC or preparative HPLC or normalphase chromatography to produce compound 9. A mixture of compound 9 andpotassium carbonate in methanol is stirred at room temperature undernitrogen. The reaction mixture is concentrated under reduced pressureand the crude product purified by routine chromatography such aspreparative TLC or preparative HPLC or normal phase chromatography toproduce compound 10.

The compounds of formula 11 may be produced from a solution of compound1 in THF to which is added a solution of R⁹-M-L (e.g. phenyl magnesiumbromide) dropwise. The reaction mixture is stirred at low temperature(e.g. 78° C. to 30° C.), and then subsequently quenched with, forexample, a saturated solution of ammonium chloride or water. The mixtureis extracted and the combined organics are dried (Na₂SO₄), filtered, andconcentrated. Suitable techniques for extraction include the use ofchloroform or dichloromethane. The crude product may be purified byroutine chromatography such as preparative TLC or preparative HPLC ornormal phase chromatography to afford the compounds of formula 11.

Examples of compounds produced in accordance with Scheme 10 are shown inTable 6, below:

TABLE 6 Example # R⁹ R⁸ 55 CH₃ (Diastereomer A) OH 55 CH₃ (DiastereomerB) OH 56 Ph (Diastereomer A) OH 56 Ph (Diastereomer B) OH 57 Et(Diastereomer A) OH 57 Et (Diastereomer B) OH 58 p-F—Ph (Diastereomer A)OH

The compound of formula 11 where NR⁶ is NH is produced from a mixture ofcompound 5a (Example 43) and R⁹-M-L (e.g. 3-ethoxy-3-oxopropylzincbromide) in THF. The reaction mixture is stirred at low temperature(−78° C.), and then subsequently quenched with, for example, a saturatedsolution of ammonium chloride. The mixture is extracted (e.g., withchloroform), and the combined organics are dried (Na₂SO₄), filtered, andconcentrated. The crude product may be purified by routinechromatography such as preparative TLC or preparative HPLC or normalphase chromatography to produce compound 11 where NR⁶ is NH.

Examples of compounds produced in accordance with Scheme 11 are shown inTable 7, below:

TABLE 7 Example # R⁹ R⁸ 59

OH

The compound of formula 5a may be produced from a mixture of compound 1and NH₄OH (0.1 mL) at room temperature, stirred under nitrogen. TheNH₄OH may be refilled and the mixture stirred again. The reactionmixture is quenched with a saturated solution of ammonium chloride andextracted with chloroform. The combined extracts may be washed withbrine, dried, filtered, and concentrated. The residue may be purified bypreparative TLC to produce compound 5a. A coupling agent (e.g.,carbonyldiimidazole) is added to a solution of compound 5a in THF atroom temperature, and the mixture stirred under nitrogen. The reactionmixture is quenched with a saturated solution of ammonium chloride andextracted. The combined extracts are washed with brine, dried, filtered,and concentrated. The residue may be purified by preparative TLC toafford compound 6.

Compounds of formula (I) may be obtained in enantiomerically enriched(R) and (S) form by crystallization with chiral salts as well known toone skilled in the art, or alternatively, may be isolated through chiralHPLC employing commercially available chiral columns.

It will be appreciated that compounds according to the present inventionmay contain asymmetric centers. These asymmetric centers mayindependently be in either the R or S configuration and such compoundsare able to rotate a plane of polarized light in a polarimeter. If saidplane of polarized light is caused by the compound to rotate in acounterclockwise direction, the compound is said to be the (−)stereoisomer of the compound. If said plane of polarized light is causedby the compound to rotate in a clockwise direction, the compound is saidto be the (+) stereoisomer of the compound. It will be apparent to thoseskilled in the art that certain compounds useful according to theinvention may also exhibit geometrical isomerism. It is to be understoodthat the present invention includes individual geometrical isomers andstereoisomers and mixtures thereof, including racemic mixtures, ofcompounds of formula (I) hereinabove. Such isomers can be separated fromtheir mixtures, by the application or adaptation of known methods, forexample chromatographic techniques and recrystallization techniques, orthey are separately prepared from the appropriate isomers of theirintermediates.

The present invention provides compositions containing the compoundsdescribed herein, including, in particular, pharmaceutical compositionscomprising therapeutically effective amounts of the compounds andpharmaceutically acceptable carriers and cosmetic compositionscomprising the compounds of the present invention.

In addition, the compounds or compositions of the present invention canbe used as a food or beverage additive for human or animal consumption

It is a further object of the present invention to provide kits having aplurality of active ingredients (with or without carrier) which,together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another object of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes a plurality of activeingredients which may be utilized in accordance with the invention.

The present invention also provides kits or single packages combiningone or more active ingredients useful in treating the infection. A kitmay provide (alone or in combination with a pharmaceutically acceptablediluent or carrier) the compounds of formula I and an additional activeingredient (alone or in combination with diluent or carrier), asdescribed above.

The products according to the present invention may be presented informs permitting administration by the most suitable route and theinvention also relates to pharmaceutical compositions containing atleast one product according to the invention which are suitable for usein human or veterinary medicine. These compositions may be preparedaccording to the customary methods, using one or more pharmaceuticallyacceptable adjuvants or excipients. The adjuvants comprise, inter alia,diluents, sterile aqueous media, and the various non-toxic organicsolvents. The compositions may be presented in the form of tablets,pills, granules, powders, aqueous solutions or suspensions, injectablesolutions, elixirs or syrups, and can contain one or more agents chosenfrom the group comprising sweeteners, flavorings, colorings, orstabilizers in order to obtain pharmaceutically acceptable preparations.

The formulations of compounds of formula I include those suitable fororal, parenteral (including subcutaneous, intradermal, intramuscular,intraperitoneal, intravenous, and intraarticular), rectal, colonic, andtopical (including dermal, buccal, nasal, sublingual, and intraocular)administration. The most suitable route may depend upon the conditionand disorder of the recipient. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. Such methods include the step ofbringing into association a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof (“active ingredient”) with thecarrier, which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary, or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active, ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed, or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques. “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Pharmaceutical compositions may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must be compatible with the compoundof formula I to insure the stability of the formulation. The compositionmay contain other additives as needed, including for example lactose,glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose,maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol,mannitol, myoinositol, and the like, and hydrates thereof, and aminoacids, for example alanine, glycine and betaine, and peptides andproteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptablecarriers and the pharmaceutically acceptable inert carriers and theaforementioned additional ingredients include, but are not limited tobinders, fillers, disintegrants, lubricants, anti-microbial agents, andcoating agents.

The dose range for adult humans is generally from 0.001 mg to 10 gdayorally. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of compound of formula I whichis effective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. Theprecise amount of compound administered to a patient will be theresponsibility of the attendant physician. It will be understood,however, that the specific dose level for any particular patient willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diet timeof administration, route of administration, rate of excretion, drugcombination and the severity of the particular disease undergoingtherapy.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may vary fromabout 5 to about 95% of the total composition.

A dosage unit (e.g. an oral dosage unit) can include from, for example,0.01 to 0.1 mg, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 0.01 mg,1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg) of a compound described herein.

The products according to the present invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

For additional information about pharmaceutical compositions and theirformulation, see, for example, Remington, The Science and Practice ofPharmacy, 20^(th) Edition (2000), which is hereby incorporated byreference in its entirety.

The compounds of formula I can be administered, e.g., by intravenousinjection, intramuscular injection, subcutaneous injection,intraperitoneal injection, topical, sublingual, intraarticular (in thejoints), intradermal, buccal, ophthalmic (including intraocular),intranasally (including using a cannula), or by other routes. Thecompounds of formula I can be administered orally, e.g., as a tablet orcachet containing a predetermined amount of the active ingredient, gel,pellet, paste, syrup, bolus, electuary, slurry, capsule, powder,granules, as a solution or a suspension in an aqueous liquid or anon-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oilliquid emulsion, via a micellar formulation (see, e.g. PCT PublicationNo. WO 97/11682, which is hereby incorporated by reference in itsentirety) via a liposomal formulation (see, e.g., European Patent EP736299 and PCT Publication Nos. WO 99/59550 and WO 97/13500, which arehereby incorporated by reference in their entirety), via formulationsdescribed in PCT Publication No. WO 03/094886, which is herebyincorporated by reference in its entirety, or in some other form. Thecompounds of formula I can also be administered transdermally (i.e. viareservoir-type or matrix-type patches, microneedles, thermal poration,hypodermic needles, iontophoresis, electroporation, ultrasound or otherforms of sonophoresis, jet injection, or a combination of any of thepreceding methods (Prausnitz et al., Nature Reviews Drug Discovery 3:115(2004), which is hereby incorporated by reference in its entirety)). Thecompounds can be administered locally, for example, at the site ofinjury to an injured blood vessel. The compounds can be coated on astent. The compounds can be administered using high-velocity transdermalparticle injection techniques using the hydrogel particle formulationdescribed in U.S. Patent Publication No. 20020061336, which is herebyincorporated by reference in its entirety. Additional particleformulations are described in PCT Publication Nos. WO 00/45792, WO00/53160, and WO 02/19989, which are hereby incorporated by reference intheir entirety. An example of a transdermal formulation containingplaster and the absorption promoter dimethylisosorbide can be found inPCT Publication No. WO 89/04179, which is hereby incorporated byreference in its entirety. PCT Publication No. WO 96/11705, which ishereby incorporated by reference in its entirety, provides formulationssuitable for transdermal administration.

The compounds can be administered in the form a suppository or by othervaginal or rectal means. The compounds can be administered in atransmembrane formulation as described in PCT Publication No. WO90/07923, which is hereby incorporated by reference in its entirety. Thecompounds can be administered non-invasively via the dehydratedparticles described in U.S. Pat. No. 6,485,706, which is herebyincorporated by reference in its entirety. The compound can beadministered in an enteric-coated drug formulation as described in PCTPublication No. WO 02/49621, which is hereby incorporated by referencein its entirety. The compounds can be administered intranasaly using theformulation described in U.S. Pat. No. 5,179,079, which is herebyincorporated by reference in its entirety. Formulations suitable forparenteral injection are described in PCT Publication No. WO 00/62759,which is hereby incorporated by reference in its entirety. The compoundscan be administered using the casein formulation described in U.S.Patent Publication No. 20030206939 and PCT Publication No. WO 00/06108,which are hereby incorporated by reference in their entirety. Thecompounds can be administered using the particulate formulationsdescribed in U.S. Patent Application Publication No. 20020034536, whichis hereby incorporated by reference in its entirety.

The compounds, alone or in combination with other suitable components,can be administered by pulmonary route utilizing several techniquesincluding but not limited to intratracheal instillation (delivery ofsolution into the lungs by syringe), intratracheal delivery ofliposomes, insufflation (administration of powder formulation by syringeor any other similar device into the lungs) and aerosol inhalation.Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers(MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasalapplications. Aerosol formulations are stable dispersions or suspensionsof solid material and liquid droplets in a gaseous medium and can beplaced into pressurized acceptable propellants, such ashydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixturethereof), dichlorodifluoromethane (or other chlorofluorocarbonpropellants such as a mixture of Propellants 11, 12, and/or 114),propane, nitrogen, and the like. Pulmonary formulations may includepermeation enhancers such as fatty acids, and saccharides, chelatingagents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g.,glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g.,benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5%but possibly up to 20%, by weight). Ethanol is commonly included inaerosol compositions as it can improve the function of the meteringvalve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include butare not limited to bile salts and those described in U.S. Pat. No.6,524,557 and references therein, which is hereby incorporated byreference in its entirety. The surfactants described in U.S. Pat. No.6,524,557, which is hereby incorporated by reference in its entirety,e.g., a C₈-C₁₆ fatty acid salt, a bile salt, a phospholipid, or alkylsaccharide are advantageous in that some of them also reportedly enhanceabsorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising atherapeutically effective amount of active compound blended with anappropriate carrier and adapted for use in connection with a dry-powderinhaler. Absorption enhancers that can be added to dry powderformulations of the present invention include those described in U.S.Pat. No. 6,632,456, which is hereby incorporated by reference in itsentirety. PCT Publication No. WO 02/080884, which is hereby incorporatedby reference in its entirety, describes new methods for the surfacemodification of powders. Aerosol formulations may include U.S. Pat. No.5,230,884, U.S. Pat. No. 5,292,499, PCT Publication No. WO 01/78694, PCTPublication No. WO 01/78696, U.S. Patent Application Publication No.2003019437, U.S. Patent Application Publication No. 20030165436, and PCTPublication No. WO 96/40089 (which includes vegetable oil), which arehereby incorporated by reference in their entirety. Sustained releaseformulations suitable for inhalation are described in U.S. PatentApplication Publication Nos. 20010036481A1, 20030232019A1, and20040018243A1 as well as in PCT Publication Nos. WO 01/13891, WO02/067902, WO 03/072080, and WO 03/079885, which are hereby incorporatedby reference in their entirety.

Pulmonary formulations containing microparticles are described in PCTPublication No. WO 03/015750, U.S. Patent Application Publication No.20030008013, and PCT Publication No. WO 0000176, which are herebyincorporated by reference in their entirety. Pulmonary formulationscontaining stable glassy state powder are described in U.S. PatentApplication Publication No. 20020141945 and U.S. Pat. No. 6,309,671,which are hereby incorporated by reference in their entirety. Otheraerosol formulations are described in EP 1338272A1, PCT Publication No.WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, PCTPublication No. WO 91/04011, and U.S. Pat. No. 6,294,153, which arehereby incorporated by reference in their entirety, and U.S. Pat. No.6,290,987, which is hereby incorporated by reference in its entirety,describes a liposomal based formulation that can be administered viaaerosol or other means.

Powder formulations for inhalation are described in U.S. PatentApplication Publication No. 20030053960 and PCT Publication No. WO0160341, which are hereby incorporated by reference in their entirety.The compounds can be administered intranasally as described in U.S.Patent Application Publication No. 20010038824, which is herebyincorporated by reference in its entirety.

Solutions of medicament in buffered saline and similar vehicles arecommonly employed to generate an aerosol in a nebulizer. Simplenebulizers operate on Bernoulli's principle and employ a stream of airor oxygen to generate the spray particles. More complex nebulizersemploy ultrasound to create the spray particles. Both types are wellknown in the art and are described in standard textbooks of pharmacysuch as Sprowls' American Pharmacy and Remington's The Science andPractice of Pharmacy, which are hereby incorporated by reference intheir entirety.

Other devices for generating aerosols employ compressed gases, usuallyhydrofluorocarbons and chlorofluorocarbons, which are mixed with themedicament and any necessary excipients in a pressurized container,these devices are likewise described in standard textbooks such asSprowls and Remington, which are hereby incorporated by reference intheir entirety.

Compounds of formula I can be incorporated into a liposome to improvehalf-life. Compounds of formula I can also be conjugated to polyethyleneglycol (PEG) chains. Methods for pegylation and additional formulationscontaining PEG-conjugates (i.e. PEG-based hydrogels, PEG modifiedliposomes) can be found in Harris et al., Nature Reviews Drug Discovery,2:214-221 (2003) and the references therein, which are herebyincorporated by reference in their entirety. Compounds of formula I canalso be administered via a nanocochleate or cochleate delivery vehicle(BioDelivery Sciences International, Raleigh, N.C.). Compounds offormula I can also be delivered using nanoemulsion formulations.

EXAMPLES

The Examples set forth below are for illustrative purposes only and arenot intended to limit, in any way, the scope of the present invention.

Example 1 Analytical Methods and Materials

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on Bruker spectrometers at 300, 400, or 500 MHz. Spectraare given in ppm (6) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Mass spectrawere collected using either a Finnigan LCQ Duo LC-MS ion trapelectrospray ionization (ESI) or a mass Varian 1200 L single quadrapolemass spectrometer (ESI). High performance liquid chromatograph (HPLC)analyses were obtained using a Luna C18(2) column (250×4.6 mm,Phenomenex, Torrance, Calif.) with UV detection at 223 nm using astandard solvent gradient program (Method A or Method B).

Method A:

Time Flow (min) (mL/min) % A % B 0 1.0 100 0 25 1.0 0 100 30 1.0 0 10035 1.0 100 0 A = Water with 0.05% Trifluoroacetic Acid B = Acetonitrilewith 0.05% TrifluoroaceticAcid

Method B:

Time Flow (min) (mL/min) % A % B 0 1.0 90 10 15 1.0 10 90 25 1.0 10 9030 1.0 90 10 A = Water with 0.05% Trifluoroacetic Acid B = Acetonitrilewith 0.05% Trifluoroacetic Acid

Example 2 Preparation of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateis a natural product derived from the fermentation of an actinomycesstrain, Streptomyces sp. AMRI-7957, deposited in an internationaldepositary authority (IDA) collection according to the Budapest Treaty.The strain AMRI-7957 was mailed on Jun. 22, 2010 to the ATCC PatentCollection by Federal Express Priority Overnight Mail with TrackingNumber 793661147245. The strain AMRI-7957 was received by ATCC on Jun.23, 2010 and assigned ATCC Accession No. PTA-11098.

a) Production of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatevia Fermentation

Typical methods for production of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatevia fermentation of Streptomyces sp. AMRI-7957 are exemplified asfollows:

The inoculum for a 500 L pilot scale production fermentation wasprepared in three stages. A frozen spore suspension of the producingorganism was initially cultured in a 250 ml shaking flask containing 50ml of an aqueous medium consisting of (per liter): 11.0 g glucose, 20.0g soluble starch, 5.0 g NZ amine, 5.0 g yeast extract and 1.0 g ofCaCO₃. The culture was grown for 45-50 hours at 28° C. and a shakingspeed of 250 rpm. This stage I culture was then transferred to asecondary seed culture in a 2.8 L flask containing 600 ml of the samemedium and grown for another 45-50 hours under the same conditions. Thestage II flask culture was then transferred to a final 20 L stage IIIseed fermentor containing 15 liters of the same growth medium. Operatingparameters for the stage III seed fermentor were as follows: temperature(28° C.), agitation (300-350 rpm), airflow (6 liters/min) andback-pressure (10 psig). After approximately 45-50 hours the stage IIIseed culture was used to inoculate a 650 liter fermentor containing 450liters of a production medium consisting of (per liter); 10.5 galpha-lactose monohydrate, 30.0 g starch, 10.0 g Nutrisoy 7B, 6.0 gCaSO₄ 2H₂O, 5.0 g CaCO₃ and 0.2 ml of antifoam (MAZU). The operatingconditions for the production fermentor were as follow: temperature (28°C.), agitation (80 rpm), airflow (50 L/min) and back-pressure (10 psig).Sterile glucose was fed during the fermentation to maintain a glucoseconcentration of 2-10 g/L. In addition, 1-2 liters of sterile soybeanoil was feed over the first 48 hours of the fermentation. The targetproduct, (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate,accumulated over the course of 10-12 days, achieving titers of 250-275mg/L.

b) Recovery and Purification of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatefrom Fermentation

The product (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatewas detected both in solution (20%) and associated with the biomass(80%). For maximum recovery of the product, these two fractions wereprocessed separately in the primary recovery steps, as exemplifiedbelow. The fermentation broth was first cooled to 20° C. and then passedthrough a continuous centrifuge resulting in about 50 Kg of cell solidsand 400 liters of supernatant.

c) Recovery of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatefrom Fermentation Supernatant

5 Kg (wet weight) of hydrated HP20 adsorbent resin was added to the 400L of supernatant and agitated for 12-16 hours during which time theproduct was almost entirely bound to the resin. The resin was recoveredby sieving (50 mesh). The resin was sequentially washed in a columnformat with 8 column volumes of water, 4 column volumes of 15%acetonitrile and 4 column volumes of 20% acetonitrile with only minimalproduct losses in the washes. The product was then eluted inapproximately 1-2 column volumes of either 100% acetone or 100%acetonitrile. Elution fractions containing the bulk of the product werepooled and evaporate under vacuum to a thick reddish brown slurry. Thisslurry was then dissolved in a minimum volume (approximately 3-5 liters)of ethyl acetate. The ethyl acetate extract was washed with an equalvolume of water followed by a equal volume of saturated solution ofNaCl. The ethyl acetate extract was further dewatered by passing over abed of anhydrous sodium sulfate. Substantially pure (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatewas then crystallized out of the ethyl acetate by chilling to 4° C.,reducing under vacuum and/or the addition of incremental volumes ofhexane and then recovered by filtration.

d) Recovery of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatefrom Fermentation Biomass

To the fermentation cell solids recovered as described in step b), eightliters of acetonitrile was first added to 50 kg of biomass and allowedto contact for 30 minutes. 25-30 liters of ethyl acetate was then addedto the biomass/acetonitrile and agitated for 12-16 hours. The liquidcontaining ethyl acetate, acetonitrile and some water was siphoned awayfrom the biomass and concentrated under vacuum to about ⅓^(rd) thestarting volume. The aqueous layer was removed in a separatory funnel.The organic layer was washed twice with equal volumes of water to pullaway any acetonitrile and then washed a 3^(rd) time with saturatedsolution of NaCl. The washed ethyl acetate extract was then furtherdewatered with anhydrous sodium sulfate and the product is crystallizedout and recovery in a manner identical to the ethyl acetate extract fromthe HP20 resin as described in step c). Additional material may berecovered with repeated extractions of the biomass.

e) Genotypic and Phenotypic Analysis

Strain AMRI-7957, the producer of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate,was characterized genotypically to determine its taxonomic position.Using a 1088 bp fragment of the 16S rDNA gene, AMRI-7957 was compared tothe NCBI database via a BLAST search. The results of this search placedAMRI-7957 in the genus Streptomyces, with the closest match beingStreptomyces scabrisporus. A representative of Streptomycesscabrisporus, NRRL B-24202, was obtained from the USDA AgriculturalResearch Service Culture Collection.

Because the structure of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateis consistent with that of SF2446A1 (Japanese Patent Nos. JP 01096189 Aand JP 63154695 A and Takeda et al., J. Antibiotics, 41(4): 417-424(1988), which are hereby incorporated by reference in their entirety)and that of mycorhodin, phenotypic tests were used to compare AMRI-7957,with SF2446 and ATCC 12644, the producers of SF2446A1 and mycorhodin,respectively. Streptomyces scabrisporus NRRL B-24202 was also includedin the phenotypic comparison because of its close relationship toAMRI-7957. Strain SF2446 was not available, so the phenotypic testscarried out as described herein were performed on the other threestrains and the results compared.

Morphological observations of strains AMRI-7957, ATCC 12644, and NRRLB-24202 were made on cultures grown at 28° C. for 21 days on inorganicsalts-starch agar (ISP medium 4), using a 40× long-working distanceobjective. Vegetative mycelium was well-developed and branched, with nofragmentation for all cultures. Strain AMRI-7957 produced aerialmycelium with long (>50 spores), branching, flexuous spore chains,usually terminating in loose spirals. While the morphologicaldescription of SF2446 and the observed morphology of ATCC 12644 weresimilar to AMRI-7957, the morphology of NRRL B-24202 was distinctlydifferent, with long, flexous, branching spore chains arising directlyfrom the substrate, with no observed hooks or coils. The production of abrown (melanoid) pigment on tyrosine agar, oatmeal agar, yeast-maltextract agar, and Bennett's agar is one feature that clearlydistinguishes strain AMRI-7957 from SF2446 and NRRL B-24202, neither ofwhich produced any pigments. ATCC 12644 produced melanoid pigments onthe same four media as AMRI-7957 and three additional characterizationmedia. Other cultural characteristics also varied from medium to mediumfor the four strains, including level of growth and aerial myceliumcolor and quantity. Additional tests also gave variable results betweenthe four strains. Notably, AMRI-7957 and the other three strains differin both the growth temperature range (32° C. maximum vs. ≧35° C.maximum) and NaCl tolerance (AMRI-7957 is more sensitive to NaCl thanany of the other strains, with growth totally inhibited in the presenceof 4% NaCl). Although the carbon utilization profile for AMRI-7957 isvery similar to that of SF2446, with only two carbon sources (glucoseand glycerol) utilized well, the other two strains had very differentprofiles, with NRRL-B-24202 utilizing seven of the eleven carbon sourcesand ATCC 12644 utilizing all eleven carbon sources tested.

Example 3 General Procedure for Alkylation of 1-Hydroxyl Group in(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Method A: A mixture of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and RX (0.15mmol) in acetone (1 mL) was heated under reflux until completion. Thecompletion was reached as shown by LC-MS or TLC analysis. The reactionmixture was cooled to room temperature and the product 2c was purifiedby preparative TLC. In some cases re-purification by semi-preparativeHPLC was necessary.

Method B: A mixture of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.05 mmol), potassium carbonate (21 mg, 0.15 mmol) and RX (0.15mmol) in DMF (1 mL) was stirred at room temperature until completion.The completion was reached as shown by LC-MS or TLC analysis. Thereaction mixture was quenched with water (5 mL) and extracted with ethylacetate (3×). The combined extracts were dried over sodium sulfate andconcentrated. The product 2c was then purified by preparative TLC. Insome cases re-purification by semi-preparative HPLC was necessary.

Example 4 Preparation of (6R,6aS,14aR)-Methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a-dimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(25 mg, 0.035 mmol), potassium carbonate (15 mg, 0.11 mmol) andiodomethane (7 μL, 0.11 mmol), the product was purified by preparativeTLC (silica gel, 95:5 dichloromethane/methanol) to afford(6R,6aS,14aR)-methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a-dimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(12 mg, 48%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 14.15 (s, 1H),8.11 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.88 (s, 1H), 5.04(br s, 1H), 4.96 (dd, J=10.3, 6.6 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 4.54(d, J=10.6 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.74-3.71 (m, 1H), 3.69(dd, J=3.1, 1.2 Hz, 1H), 3.60 (s, 3H), 3.59 (s, 3H), 3.61-3.56 (m, 1H),3.40 (s, 3H), 3.39-3.33 (m, 2H), 3.12 (t, J=9.2 Hz, 1H), 2.47 (d, J=4.6Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 712 (M+H);HPLC 95.9% (AUC), t_(R) 12.66 min.

Example 5 Preparation of (6R,6aS,14aR)-Methyl6,14a-dihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a,8-trimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (42 mg, 0.30 mmol) andiodomethane (14 μL, 0.15 mmol), the product was purified by preparativeTLC (silica gel, 95:5 dichloromethane/methanol) followed bysemi-preparative HPLC (45:55 acetonitrile/water with 0.05% TFA) toafford (6R,6aS,14aR)-methyl6,14a-dihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6a,8-trimethoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(8 mg, 23%) as an orange-yellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.49(s, 0.3H), 8.45 (s, 0.7H), 6.83 (s, 0.3H), 6.82 (s, 0.7H), 6.52 (d,J=9.1 Hz, 0.7H), 5.90 (d, J=6.0 Hz, 0.3H), 6.23 (s, 0.3H), 5.96 (s,0.7H), 4.96 (d, J=6.4 Hz, 1H), 4.66 (d, J=8.3 Hz, 1H), 4.23 (br s, 1H),3.96-3.91 (m, 0.7H), 3.85-3.83 (m, 0.3H), 3.85 (s, 0.9H), 3.84 (s,2.1H), 3.82 (s, 0.9H), 3.81 (s, 2.1H), 3.79 (s, 3H), 3.74 (dd, J=9.4,3.2 Hz, 1H), 3.70-3.69 (m, 1H), 3.64-3.63 (m, 1H), 3.61 (s, 2.1H), 3.60(s, 2.1H), 3.56 (s, 0.9H), 3.55 (s, 0.9H), 3.38 (s, 2.1H), 3.37 (s,0.9H), 3.40-3.33 (m, 3H), 3.14-3.10 (m, 1H), 2.20 (s, 0.9H), 2.19 (s,2.1H), 1.35 (d, J=6.1 Hz, 2.1H), 1.28 (d, J=6.2 Hz, 0.9H); MS (ESI+) m/z726 (M+H); HPLC 93.4% (AUC), t_(R) 14.84, 15.04 min.

Example 6 Preparation of (6R,6aS,14aR)-Methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-1-(2-methoxy-2-oxoethoxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(50 mg, 0.072 mmol), potassium carbonate (30 mg, 0.22 mmol) and methylbromoacetate (20 μL, 0.22 mmol), the product was purified by preparativeTLC (silica gel, 95:5 dichloromethane/methanol) and semi-preparativeHPLC (45:55 acetonitrile/water with 0.05% TFA) to afford(6R,6aS,14aR)-methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-1-(2-methoxy-2-oxoethoxy)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(10 mg, 20%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.19 (s, 1H),8.27 (s, 1H), 6.89 (d, J=9.0 Hz, 1H), 6.86 (s, 1H), 5.88 (s, 1H), 4.96(d, J=6.6 Hz, 1H), 4.69 (d, J=8.7 Hz, 1H), 4.54 (d, J=15.1 Hz, 1H), 4.43(d, J=15.1 Hz, 1H), 3.91 (br s, 3H), 3.79 (s, 3H), 3.76-3.67 (m, 3H),3.73 (s, 3H), 3.64-3.55 (m, 1H), 3.60 (s, 3H), 3.39 (s, 3H), 3.36-3.29(m, 3H), 3.13 (t, J=9.2 Hz, 1H), 2.60 (br s, 1H), 2.19 (s, 3H), 1.36 (d,J=6.2 Hz, 3H); MS (ESI+) m/z 770 (M+H); HPLC 96.4% (AUC), t_(R) 15.46min

Example 7 Preparation of (6R,6aS,14aR)-Methyl1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzylbromide (18 μL, 0.15 mmol), the product was purified by preparative TLC(silica gel, 95:5 dichloromethane/methanol) to afford(6R,6aS,14aR)-methyl1-(benzyloxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(18 mg, 45%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 14.17 (s, 1H),7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.40-7.38 (m, 1H), 7.34-7.32 (m, 2H),6.85 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 5.86 (s, 1H), 5.07 (br s, 1H),4.98-4.94 (m, 1H), 4.93 (d, J=11.3 Hz, 1H), 4.82 (d, J=11.3 Hz, 1H),4.68 (d, J=8.8 Hz, 1H), 4.54 (d, J=10.5 Hz, 1H), 3.82 (s, 3H), 3.74-3.72(m, 2H), 3.65-3.62 (m, 1H), 3.60 (s, 3H), 3.54 (s, 3H), 3.51-3.38 (m,1H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.0 Hz, 1H), 2.48 (d,J=4.1 Hz, 1H), 2.19 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 788(M+H); HPLC 95.4% (AUC), t_(R) 14.56 min.

Example 8 Preparation of (6R,6aS,14aR)-Methyl1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and benzylbromoacetate (24 μL, 0.15 mmol), the product was purified by preparativeTLC (silica gel, 95:5 dichloromethane/methanol) to afford(6R,6aS,14aR)-methyl1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(22 mg, 51%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 14.18 (s, 1H),8.29 (s, 1H), 7.44-7.31 (m, 5H), 6.88 (d, J=8.7 Hz, 1H), 6.85 (s, 1H),5.87 (s, 1H), 5.40 (d, J=12.2 Hz, 1H), 5.31 (d, J=12.2 Hz, 1H), 5.00 (s,1H), 4.95 (dd, J=9.9, 7.3 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H), 4.54 (d,J=15.2 Hz, 1H), 4.48 (br s, 1H), 4.45 (br s, 1H), 3.78 (s, 3H),3.76-3.71 (m, 1H), 3.69 (d, J=1.6 Hz, 1H), 3.60-3.54 (m, 2H), 3.60 (s,6H), 3.39 (s, 3H), 3.36-3.32 (m, 1H), 3.13 (t, J=9.2 Hz, 1H), 2.47 (d,J=4.5 Hz, 1H), 2.18 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 846(M+H); HPLC 94.4% (AUC), t_(R) 18.76 min

Example 9 Preparation of2-06R,6aS,14aR)-6,8,14a-Trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-1-yloxy)aceticacid

A mixture of (6R,6aS,14aR)-methyl1-(2-(benzyloxy)-2-oxoethoxy)-6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(22 mg, 0.024 mmol) and 10% PdC (10 mg) in THF (1 mL) was stirred underhydrogen (1 atm) at room temperature for 1 h. The reaction mixture wasfiltered and concentrated. The residue was purified by semi-preparativeHPLC (45:55 acetonitrile/water with 0.05% TFA) to afford2-((6R,6aS,14aR)-6,8,14a-trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-1-yloxy)aceticacid (13 mg, 66%) as an orange solid and as a mixture of diastereomers:¹H NMR (500 MHz, acetone-d₆) δ 14.30 (br s, 1H), 8.21 (s, 0.5H), 8.17(s, 0.5H), 7.19 (d, J=9.0 Hz, 0.5H), 7.08 (d, J=5.7 Hz, 0.5H), 6.99 (s,0.5H), 6.91 (s, 0.5H), 6.17 (s, 0.5H), 6.00 (s, 0.5H), 5.30 (br s, 1H),5.11 (d, J=4.8 Hz, 0.5H), 5.06 (d, J=4.8 Hz, 0.5H), 4.92-4.85 (m, 0.5H),4.76-4.72 (m, 0.5H), 4.62 (br s, 0.5H), 4.60 (br s, 0.5H), 4.50-4.41 (m,1H), 4.04 (d, J=5.1 Hz, 1H), 3.91-3.83 (m, 1H), 3.76 (s, 1.5H), 3.75 (s,1.5H), 3.74 (br s, 3H), 3.54 (br s, 3H), 3.52 (s, 1.5H), 3.50 (s, 1.5H),3.32-3.30 (m, 1H), 3.09-3.05 (m, 1H), 2.19 (s, 1.5H), 2.17 (s, 1.5H),1.25 (d, J=6.2 Hz, 1.5H), 1.21 (d, J=6.3 Hz, 1.5H); MS (ESI+) m/z 756(M+H); HPLC 98.5% (AUC), t_(R) 11.48, 11.45 min.

Example 10 Preparation of (6R,6aS,14aR)-Methyl1-(2-amino-2-oxoethoxy)-6,8,14a-trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method A using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) andbromoacetamide (21 mg, 0.15 mmol), the product was purified bypreparative TLC (silica gel, 95:5 dichloromethane/methanol) andpreparative HPLC (45:55 acetonitrile/water with 0.05% TFA) to afford(6R,6aS,14aR)-methyl1-(2-amino-2-oxoethoxy)-6,8,14a-trihydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(6 mg, 15%) as an orange-red solid and as a mixture of diastereomers: ¹HNMR (500 MHz, CDCl₃) δ 14.27 (s, 0.3H), 14.21 (s, 0.7H), 8.12 (s, 0.3H),8.11 (s, 0.7H), 6.90 (br s, 1H), 6.22 (br s, 1H), 5.94 (br s, 1H), 5.91(s, 0.7H), 5.90 (s, 0.3H), 5.14 (d, J=4.5 Hz, 0.3H), 4.97 (d, J=6.7 Hz,0.7H), 4.75 (d, J=14.7 Hz, 0.3H), 4.48 (d, J=14.7 Hz, 0.7H), 4.70 (br s,1H), 4.21 (d, J=14.7 Hz, 1H), 3.81-3.80 (m, 1H), 3.81 (s, 3H), 3.78 (brs, 2H), 3.74-3.70 (m, 2H), 3.65-3.56 (m, 1H), 3.61 (s, 3H), 3.40 (s,3H), 3.36 (s, 3H), 3.13 (t, J=9.2 Hz, 1H), 2.21 (s, 3H), 1.36 (d, J=6.1Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC>99% (AUC), t_(R) 13.72 min.

Example 11 Preparation of (6R,6aS,14aR)-Methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(pyridin-3-ylmethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatehydrochloride

Following General Procedure: Method B using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and3-picolyl chloride hydrochloride (25 mg, 0.15 mmol), the product waspurified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)and converted to hydrochloride to afford (6R,6aS,14aR)-methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(pyridin-3-ylmethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatehydrochloride (13 mg, 31%) as an orange-red solid: ¹H NMR (500 MHz,CDCl₃) δ 14.21 (s, 1H), 8.79 (br s, 2H), 8.26 (d, J=4.1 Hz, 1H), 7.87(br s, 1H), 7.41 (s, 1H), 6.92 (s, 1H), 6.89 (br s, 1H), 5.85 (s, 1H),5.12 (d, J=11.2 Hz, 1H), 5.05 (d, J=11.3 Hz, 1H), 4.98 (br s, 1H), 4.66(br s, 1H), 4.39 (br s, 1H), 3.85 (s, 3H), 3.81-3.74 (m, 1H), 3.72 (s,3H), 3.65 (dd, J=19.3, 7.3 Hz, 1H), 3.60 (s, 3H), 3.43 (s, 1H), 3.40 (s,3H), 3.36-3.31 (m, 1H), 3.14 (t, J=9.0 Hz, 1H), 2.51 (br s, 1H), 2.24(s, 3H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 789 (M+H); HPLC>99%(AUC), t_(R) 12.34 min.

Example 12 Preparation of (6R,6aS,14aR)-Methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Following General Procedure: Method B using (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product waspurified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)to afford (6R,6aS,14aR)-methyl6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(31 mg, 75%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 14.17 (s, 1H),8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82(d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m,2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60(s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54(br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d,J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), t_(R) 16.81min

Example 13 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in DMSO (1 mL) was added lithium chloride (121 mg,2.87 mmol). The reaction mixture was irradiated with microwaves at 120°C. for 21 min. The crude material was purified by preparative HPLC(10:90 acetonitrile/water to 100% acetonitrile with 0.05% TFA over 50min) to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-(2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (12.0 mg, 12.5%) as a dark orange-red solid: ¹H NMR (500 MHz,acetone-d₆) δ 14.27 (s, 1H), 8.06 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.62(s, 1H), 6.00 (s, 2H), 5.09-5.05 (m, 1H), 4.90-4.83 (m, 1H), 4.78-4.71(m, 1H), 4.55-4.43 (m, 1H), 3.86-3.82 (m, 1H), 3.74 (s, 3H), 3.73-3.70(m, 1H), 3.54 (s, 3H), 3.53-3.45 (m, 2H), 3.32 (s, 3H), 3.30-3.20 (m,2H), 3.06 (t, J=9.1 Hz, 2H), 2.43 (s, 3H), 1.19 (d, J=6.0 Hz, 3H); MS(ESI+) m/z 684 (M+H); HPLC 93.4% (AUC), t_(R) 11.84 min

Example 14 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (100 mg, 0.14 mmol) in THF (3 mL) was addedpolystyrene-carbodiimide (261 mg, 0.29 mmol), 1-hydroxybenzotriazolehydrate (39 mg, 0.29 mmol) and aniline (127 mg, 1.43 mmol). The reactionmixture was stirred at room temperature under nitrogen for 6 h. Thereaction was filtered through a micro filter. The crude material waspurified by preparative TLC (silica gel, 90:10 chloroform/methanol) andpreparative HPLC (10:90 acetonitrile/water to 100% acetonitrile with0.05% TFA over 50 min) to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamideas a mixture of diastereomers (5.0 mg, 4%) and as a red solid: ¹H NMR(500 MHz, CDCl₃) δ 14.25 (s, 0.3H), 14.19 (s, 0.7H), 11.64 (br s, 1H),8.28 (s, 0.3H), 8.24 (s, 0.7H), 7.50-7.42 (m, 3H), 7.38-7.32 (m, 3H),7.16 (t, J=14.0 Hz, 2H), 6.91 (d, J=8.5 Hz, 0.3H), 6.86 (d, J=8.5 Hz,0.7H), 6.54 (s, 1H), 6.20 (s, 0.3H), 6.18 (s, 0.7H), 5.85 (s, 1H),5.18-5.13 (m, 1H), 4.98 (d, J=8.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.81 (s,3H), 3.79 (s, 2H), 3.60 (s, 3H), 3.56-3.51 (m, 2H), 3.44 (s, 2H), 3.38(s, 1H), 3.15-3.10 (m, 1H), 2.51 (s, 3H), 1.37 (d, J=6.0 Hz, 3H); MS(ESI−) m/z 757 (M−H); HPLC 97.0% (AUC), t_(R) 12.95 min.

Example 15 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(4-phenylpiperazine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraonehydrochloride

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide(156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol)and 1-phenylpiperazine (21 mg, 0.13 mmol). The reaction mixture wasstirred at room temperature under nitrogen for 5 h. The reaction wasfiltered through a micro filter and concentrated. The crude material waspurified by preparative TLC (silica gel, 90:10 dichloromethane/methanol)to afford a dark red solid. The solid was dissolved in methanol (1 mL)and treated with HCl (1.25 M solution in methanol, 0.5 mL) at 0° C. Thesolution was concentrated and triturated with diethyl ether to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(4-phenylpiperazine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraonehydrochloride as a mixture of diastereomers (9.0 mg, 25%) and as a redsolid: ¹H NMR (500 MHz, CD₃OD) δ 8.10 (s, 1H), 7.60-7.20 (m, 5H), 6.70(s, 1H), 6.20-6.10 (m, 0.3H), 6.04-5.95 (m, 0.7H), 5.49 (s, 1H),4.96-4.85 (m, 1H), 4.18-4.08 (m, 1H), 4.05-3.89 (m, 1H), 3.78-3.62 (m,7H), 3.54 (s, 3H), 3.61-3.52 (m, 2H), 3.51-3.41 (m, 7H), 3.27-3.16 (m,1H), 3.09-2.90 (m, 1H), 3.16 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI−) m/z826 (M−H); HPLC 94.2% (AUC), t_(R) 11.89 min.

Example 16 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide(156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol)and dimethylamine (0.09 mL, 0.13 mmol). The reaction mixture was stirredat room temperature under nitrogen for 4 h. The reaction was filteredthrough a micro filter and concentrated. The crude material was purifiedby preparative TLC (9:1, methylene chloride/methanol) to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamideas a mixture of diastereomers (8.0 mg, 13%) and as a red solid: ¹H NMR(500 MHz, CDCl₃) δ 14.18 (s, 1H), 8.16 (s, 1H), 6.85 (d, J=9.0 Hz,0.8H), 6.57 (s, 1H), 6.28-6.24 (m, 0.2H), 6.20 (s, 0.2H), 5.87 (s,0.8H), 5.14-5.08 (m, 1H), 5.00-4.94 (m, 1H), 4.71-4.66 (m, 1H),4.62-4.56 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.61 (s, 3H),3.59-3.52 (m, 3H), 3.41 (s, 3H), 3.38-3.28 (m, 2H), 3.13 (t, J=9.0 Hz,1H), 2.92 (s, 6H), 2.14 (s, 3H), 3.14 (d, J=6.0 Hz, 3H); MS (ESI−) m/z709 (M−H); HPLC 95.6% (AUC), t_(R) 11.51 min

Example 17 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-ylmethyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamidehydrochloride

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide(156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol)and 3-(aminomethyl)pyridine (11 mg, 0.10 mmol). The reaction mixture wasstirred at room temperature under nitrogen for 7 h. The reaction wasfiltered through a micro filter and concentrated. The crude material waspurified by preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afforda dark red solid. The solid was dissolved in methanol (2 mL) and treatedwith HCl (0.20 mL, 1.25 M solution in methanol) at 0° C. The solutionwas concentrated and triturated with diethyl ether to afford6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-ylmethyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamidehydrochloride as a mixture of diastereomers (12 mg, 21%) and as a redsolid: ¹H NMR (500 MHz, CD₃OD) δ 8.84-8.80 (m, 1H), 8.80-8.65 (m, 1H),8.64-8.58 (m, 1H), 8.10 (s, 1H), 8.09-8.06 (m, 1H), 6.63 (s, 1H), 6.16(s, 0.3H), 6.01 (s, 0.7H), 5.20 (s, 0.3H), 4.95 (s, 0.7H), 4.67 (br s,1H), 3.92-3.89 (m, 1H), 3.75 (s, 3H), 3.70-3.67 (m, 0.3H), 3.64-3.62 (m,0.7H), 3.57 (s, 3H), 3.54 (s, 1H), 3.50 (s, 1H), 3.49-3.37 (m, 5H),3.24-3.17 (m, 1H), 3.10-3.02 (m, 1H), 2.23 (s, 3H), 1.28 (d, J=6.5 Hz,2H), 1.23 (d, J=6.5 Hz, 1H); MS (ESI−) m/z 772 (M−H); HPLC 96.7% (AUC),t_(R) 10.53 min.

Example 18 Preparation of(6R,6aS,14aR)—N-Cyclohexyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide(156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol)and cyclohexylamine (10 mg, 0.13 mmol). The reaction mixture was stirredat room temperature under nitrogen for 4 h. The reaction was filteredthrough a micro filter and concentrated. The crude material was purifiedby preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford(6R,6aS,14aR)—N-cyclohexyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamideas a mixture of diastereomers (14 mg, 20%) and as a dark red solid: ¹HNMR (500 MHz, CD₃OD) δ 8.10 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.3H), 6.00(s, 0.7H), 5.19 (s, 0.3H), 4.95 (s, 0.7H), 4.89 (br s, 1H), 3.95-3.90(m, 1H), 3.75 (s, 3H), 3.74-3.71 (m, 0.7H), 3.70-3.68 (m, 0.3H),3.67-3.64 (m, 1H), 3.58 (s, 3H), 3.53 (s, 1H), 3.50 (s, 2H), 3.48-3.35(m, 5H), 3.27-3.20 (m, 1H), 3.09-3.02 (m, 1H), 2.22 (s, 3H), 1.93-1.81(m, 2H), 1.80-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.40-1.33 (m, 2H), 1.27(d, J=6.5 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H), 1.19-1.15 (m, 2H); MS (ESI+)m/z 765 (M+H); HPLC 95.4% (AUC), t_(R) 13.79 min

Example 19 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% PdC and thereaction mixture was stirred at room temperature under hydrogenatmosphere for 4 h. The reaction mixture was filtered without exposureto air into another flask containing polystyrene-carbodiimide (260 mg,0.29 mmol) and the mixture was stirred for 10 min. A solution of1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) andmethylamine (0.08 mL, 2.0 M solution in THF, 0.16 mmol) were added andthe reaction mixture was stirred at room temperature under nitrogen for4 h. The reaction was filtered through a micro filter and concentrated.The crude material was purified by preparative HPLC (10:90acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10min, then isocratic) to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamideas a mixture of diastereomers (7.5 mg, 7%) and as a dark red solid: ¹HNMR (500 MHz, CD₃OD) δ 8.11 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.3H), 5.99(s, 0.7H), 5.19-5.17 (m, 0.3H), 4.94 (s, 0.7H), 3.75 (s, 3H), 3.57 (s,3H), 3.54 (s, 1H), 3.51 (s, 1H), 3.48-3.35 (m, 6H), 3.26-3.21 (m, 1H),3.08 (t, J=9.0 Hz, 0.3H), 3.04 (t, J=9.0 Hz, 0.7H), 2.78 (s, 3H), 2.22(s, 3H), 1.27 (d, J=9.0 Hz, 2H), 1.22 (d, J=6.5 Hz, 1H); MS (ESI+) m/z697 (M+H); HPLC>99% (AUC), t_(R) 10.63 min.

Example 20 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% PdC and thereaction mixture was stirred at room temperature under hydrogen at 1atmosphere for 4 h. The reaction mixture was filtered without exposureto air into another flask containing polystyrene-carbodiimide (260 mg,0.29 mmol) and the mixture was stirred for 10 min. A solution of1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) andammonia (0.22 mL, 2.0 M solution in THF, 0.16 mmol) were added and thereaction mixture was stirred at room temperature under nitrogen for 4 h.The reaction was filtered through a micro filter and concentrated. Thecrude material was purified by preparative HPLC (10:90acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10min, then isocratic) to afford6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((2S,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(12 mg, 15%) as a dark red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.19 (s,1H), 12.89 (s, 1H), 8.22 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.52 (s, 1H),5.96 (s, 2H), 5.87 (s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=9.0 Hz,1H), 3.79 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (s, 3H), 3.59-3.50 (m, 2H),3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (s, 3H),1.36 (s, 3H); MS (ESI+) m/z 683 (M+H); HPLC 94.3% (AUC), t_(R) 11.64 min

Example 21 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(piperidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid²(90 mg, 0.13 mmol) in THF (3 mL) was added polystyrene carbodiimide(0.24 g, 0.27 mmol) and 1-hydroxybenzotriazole hydrate (36 mg, 0.27mmol), and then the reaction mixture was stirred at room temperatureunder nitrogen. After 15 min, piperidine (15 mg, 0.18 mmol) was addedand the reaction mixture was stirred at room temperature under nitrogen.After 2 h, the reaction mixture was filtered and concentrated underreduced pressure. The resulting crude material was purified bypreparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/waterwith 0.05% TFA over 10 min, then isocratic). The resulting product waslyophilized from acetonitrile (3 mL) and water (1 mL) to yield(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(piperidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone(10 mg, 10%) as a mixture of diastereomers and as a dark red solid: ¹HNMR (500 MHz, CD₃OD) δ 8.10 (s, 1H), 6.64 (s, 0.8H), 6.63 (s, 0.2H),6.17-6.14 (m, 0.2H), 6.02-5.97 (m, 0.8H), 5.19 (d, J=2.0 Hz, 0.2H),4.97-4.87 (m, 2H), 4.32 (d, J=4.5 Hz, 0.8H), 3.74 (s, 3H), 3.78-3.70 (m,4H), 3.65-3.63 (m, 1H), 3.58 (s, 3H), 3.52 (d, J=15.0 Hz, 3H), 3.45-3.39(m, 5H), 3.36-3.33 (m, 2H), 3.23-3.21 (m, 2H), 3.16-3.02 (m, 1H), 2.46(s, 0.6H), 2.09 (s, 2.4H), 1.89-1.86 (m, 1H), 1.27 (d, J=6.0 Hz, 2.4H),1.22-1.21 (m, 0.6H); MS (ESI+) m/z 751 (M+H); HPLC 98.3% (AUC), t_(R)11.40 min.

Example 22 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (56 mg, 0.082 mmol) in THF (2 mL) was added polystyrenecarbodiimide (0.15 mg, 0.17 mmol) and 1-hydroxybenzotriazole hydrate (22mg, 0.16 mmol), and then the reaction mixture was stirred at roomtemperature under nitrogen. After 15 min, pyrrolidine (11 mg, 0.16 mmol)was added and the reaction mixture was stirred at room temperature undernitrogen. After 5 h, the reaction mixture was filtered and concentratedunder reduced pressure. The crude material was purified by preparativeHPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05%TFA over 10 min, then isocratic). The resulting product was lyophilizedfrom acetonitrile (3 mL) and water (1 mL) to give(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(pyrrolidine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone(1.7 mg, 2.8%) as a mixture of diastereomers and as a dark red solid: ¹HNMR (500 MHz, CD₃OD) δ 8.10 (s, 1H), 6.64 (s, 1H), 6.17 (s, 0.3H), 6.01(s, 0.7H), 4.96-4.87 (m, 2H), 3.74 (s, 3H), 3.64 (s, 1H), 3.57 (s, 3H),3.52 (d, J=18.0 Hz, 3H), 3.46-3.39 (m, 6H), 3.26-3.20 (m, 1H), 3.08-3.02(m, 2H), 2.08 (s, 3H), 1.93-1.87 (m, 4H), 1.28 (d, J=6.0 Hz, 2.1H), 1.22(d, J=6.0 Hz, 0.9H); MS (ESI+) m/z 737 (M+H); HPLC 94.4% (AUC), t_(R)10.71 min

Example 23 Preparation of(6R,6aS,14aR)—N-(Biphenyl-4-yl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (0.11 g, 0.16 mmol) in THF (2 mL) was added polystyrenecarbodiimide (0.26 g, 0.32 mmol) and 1-hydroxybenzotriazole hydrate (43mg, 0.32 mmol), and then the reaction mixture was stirred at roomtemperature under nitrogen. After 15 min, 4-aminobiphenyl (42 mg, 0.25mmol) was added and the reaction mixture was stirred at room temperatureunder nitrogen. After 3 h, the reaction mixture was filtered andconcentrated under reduced pressure. The crude material was purified bypreparative TLC (95:5 chloroform/methanol) and then by semi-preparativeHPLC (20:80 acetonitrile/water to 100% acetonitrile with 0.05% TFA over40 min). The resulting product was lyophilized from acetonitrile (3 mL)and water (1 mL) to give (6R,6aS,14aR)—N-(biphenyl-4-yl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(3.7 mg, 3.3%) as a mixture of diastereomers and as a red-orange solid:¹H NMR (500 MHz, CDCl₃) δ 14.21 (s, 1H), 11.71 (s, 0.2H), 11.64 (s,0.8H), 8.24 (s, 0.2H), 8.21 (s, 0.8H), 7.58-7.52 (m, 7H), 7.44-7.42 (m,2H), 7.36-7.33 (m, 1H), 6.85 (d, J=9.0 Hz, 0.8H), 6.60 (s, 1H), 6.21 (d,J=6.0 Hz, 0.2H), 6.18 (s, 0.2H), 5.86 (s, 0.8H), 5.24 (br s, 1H), 4.98(d, J=5.5 Hz, 1H), 4.66 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.70 (dd,J=9.5, 3.0 Hz, 1H), 3.67 (s, 1H), 3.61 (s, 3H), 3.60-3.57 (m, 1H), 3.56(d, J=13.5 Hz, 1H), 3.41 (s, 3H), 3.38-3.31 (m, 2H), 3.13-3.10 (m, 1H),2.55 (s, 3H), 1.35 (d, J=6.0 Hz, 2.4H), 1.25 (d, J=5.5 Hz, 0.6H); MS(ESI+) m/z 835 (M+H); HPLC 97.9% (AUC), t_(R) 15.37 min.

Example 24 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-(2-hydroxyethyl)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (67 mg, 0.098 mmol) in THF (3 mL) was added 10% PdC (67 mg) andthe reaction was stirred at room temperature under hydrogen (1 atm).After 5 h, the reaction was filtered into a round bottom flaskcontaining polystyrene carbodiimide (0.17 g, 0.19 mmol) in THF (2 mL)without exposure to air under argon at room temperature. To the reactionmixture, 1-hydroxybenzotriazole hydrate (27 mg, 0.20 mmol) and ethanolamine (5.7 mg, 0.093 mmol) were added and the reaction was stirred atroom temperature under argon. After 4 h, the reaction was filtered andconcentrated under reduced pressure. The crude product was purified bypreparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/waterwith 0.05% TFA over 10 min, then isocratic). The resulting product waslyophilized from acetonitrile (3 mL) and water (1 mL) to yield(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-(2-hydroxyethyl)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(4.3 mg, 6.1%) as a mixture of diastereomers and as a red-orange solid:¹H NMR (500 MHz, CD₃OD) δ 8.10 (s, 1H), 6.59 (s, 1H), 6.15 (s, 0.4H),5.99 (s, 0.6H), 4.94-4.87 (m, 2H), 3.75 (s, 3H), 3.64-3.60 (m, 3H), 3.58(s, 3H), 3.52 (d, J=14.5 Hz, 3H), 3.48-3.34 (m, 5H), 3.27-3.19 (m, 1H),3.09-3.03 (m, 1H), 2.45 (s, 3H), 1.27 (d, J=6.5 Hz, 1.8H), 1.22 (d,J=6.5 Hz, 1.2H); MS (ESI−) m/z 725 (M−H); HPLC 98.6% (AUC), t_(R) 10.05min

Example 25 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(3-phenylpropyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (71 mg, 0.10 mmol) in THF (3 mL) was added 10% PdC (84 mg) and thereaction was stirred at room temperature under hydrogen (1 atm). After 5h, the reaction was filtered into a round bottom flask containingpolystyrene carbodiimide (0.19 g, 0.21 mmol) in THF (2 mL) withoutexposure to air under argon at room temperature. To the reactionmixture, 1-hydroxybenzotriazole hydrate (27 mg, 0.20 mmol) and3-phenylpropyl amine (11 mg, 0.084 mmol) were added and the reaction wasstirred at room temperature under argon. After 4 h, the reaction wasfiltered and concentrated under reduced pressure. The resulting crudeproduct was purified by preparative HPLC (10:90 acetonitrile/water to60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic).The resulting product was lyophilized from acetonitrile (3 mL) and water(1 mL) to yield(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(3-phenylpropyl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(4.3 mg, 5.3%) as a mixture of diastereomers and as an orange-red solid:¹H NMR (500 MHz, CD₃OD) δ 8.11 (s, 1H), 7.26-7.20 (m, 3H), 7.16-7.11 (m,3H), 6.61 (s, 1H), 6.14 (s, 0.3H), 5.96 (s, 0.7H), 5.18 (s, 1H), 4.90(s, 2H), 3.74 (s, 3H), 3.57 (s, 3H), 3.52 (d, J=14.5 Hz, 3H), 3.45-3.39(m, 3H), 3.28-3.21 (m, 1H), 3.10-3.01 (m, 1H), 2.66-2.56 (m, 2H), 2.25(s, 3H), 1.82-1.76 (m, 2H), 1.26 (d, J=6.0 Hz, 2.1H), 1.21 (d, J=6.0 Hz,0.9H); MS (ESI+) m/z 801 (M+H); HPLC 98.0% (AUC), t_(R) 14.31 min.

Example 26 Preparation of(6R,6aS,14aR)—N-(4-Fluorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (74 mg, 0.11 mmol) in THF (10 mL) was added 10% PdC (0.15 g) andthe reaction was stirred at room temperature under hydrogen (1 atm).After 5 h, the reaction was filtered into a round bottom flaskcontaining polystyrene carbodiimide (0.20 g, 0.22 mmol) in THF (2 mL)without exposure to air under argon at room temperature. To the reactionmixture, 1-hydroxybenzotriazole hydrate (27 mg, 0.20 mmol) and4-fluorobenzyl amine (15 mg, 0.12 mmol) were added and the reaction wasstirred at room temperature under argon. After 5 h, the reaction wasfiltered and concentrated under reduced pressure. The resulting crudeproduct was purified by preparative HPLC (10:90 acetonitrile/water to60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) andby semi-preparative HPLC (20:80 acetonitrile/water to 100% acetonitrilewith 0.05% TFA over 40 min) The resulting product was lyophilized fromacetonitrile (3 mL) and water (1 mL) to yield(6R,6aS,14aR)—N-(4-fluorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(7.3 mg, 8.5%) as a mixture of diastereomers and as an orange-red solid:¹H NMR (500 MHz, CD₃OD) δ 8.09 (s, 0.4H), 8.08 (s, 0.6H), 7.33-7.27 (m,2H), 7.09-6.92 (m, 2H), 6.58 (s, 1H), 6.13 (s, 0.4H), 5.96 (s, 0.6H),5.20 (s, 0.4H), 4.93 (s, 0.6H), 4.90 (s, 1H), 4.44-4.32 (m, 2H), 3.75(s, 3H), 3.72-3.71 (m, 1H), 3.66-3.65 (m, 1H), 3.57 (s, 3H), 3.52 (d,J=10.0 Hz, 3H), 3.44-3.36 (m, 2H), 3.22 (d, J=18.5 Hz, 1H), 3.10-3.03(m, 1H), 2.17 (s, 2H), 2.16 (s, 1H), 1.28 (d, J=6.0 Hz, 1.8H), 1.22 (d,J=6.0 Hz, 1.2H); MS (ESI+) m/z 791 (M+H); HPLC 98.8% (AUC), t_(R) 13.31min.

Example 27 Preparation of(6R,6aS,14aR)—N-(4-Chlorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (0.11 g, 0.17 mmol) in THF (10 mL) was added 10% PdC (0.21 g) andthe reaction was stirred at room temperature under hydrogen (1 atm).After 5 h, the reaction was filtered into a round bottom flaskcontaining polystyrene carbodiimide (0.30 g, 0.33 mmol) in THF (2 mL)without exposure to air under argon at room temperature. To the reactionmixture, 1-hydroxybenzotriazole hydrate (44 mg, 0.33 mmol) and4-chlorobenzyl amine (35 mg, 0.25 mmol) were added and the reaction wasstirred at room temperature under argon. After 16 h, the reaction wasfiltered and concentrated under reduced pressure. The resulting crudeproduct was purified by preparative HPLC (10:90 acetonitrile/water to60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic).The resulting product was lyophilized from acetonitrile (3 mL) and water(1 mL) to yield(6R,6aS,14aR)—N-(4-chlorobenzyl)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(8.8 mg, 6.4%) as a mixture of diastereomers and as an orange-red solid:¹H NMR (500 MHz, CD₃OD) δ 8.10 (s, 0.3H), 8.09 (s, 0.7H), 7.29-7.23 (m,4H), 6.59 (s, 1H), 6.14 (s, 0.3H), 5.98 (s, 0.7H), 4.93-4.80 (m, 2H),4.46-4.34 (m, 2H), 3.75 (s, 3H), 3.71-3.65 (m, 1H), 3.58 (s, 3H), 3.52(d, J=13.5 Hz, 2H), 3.48-3.35 (m, 5H), 3.26 (d, J=11.5 Hz, 1H),3.10-3.03 (m, 1H), 2.19 (s, 1.4H), 2.18 (s, 0.6H), 1.27 (d, J=6.0 Hz,2.1H), 1.23 (d, J=6.5 Hz, 0.9H); MS (ESI+) m/z 807 (M+H); HPLC 98.2%(AUC), t_(R) 14.03 min.

Example 28 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N-(4-methoxybenzyl)-3-methyl-7,9-12-14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (0.11 g, 0.17 mmol) in THF (10 mL) was added 10% PdC (0.21 g) andthe reaction was stirred at room temperature under hydrogen (1 atm).After 5 h, the reaction was filtered into a round bottom flaskcontaining polystyrene carbodiimide (0.30 g, 0.33 mmol) in THF (2 mL)without exposure to air under argon at room temperature. To the reactionmixture, 1-hydroxybenzotriazole hydrate (48 mg, 0.35 mmol) and4-methoxybenzyl amine (33 mg, 0.24 mmol) were added and the reaction wasstirred at room temperature under argon. After 16 h, the reaction wasfiltered and concentrated under reduced pressure. The resulting crudeproduct was purified by preparative HPLC (10:90 acetonitrile/water to60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic).The resulting product was lyophilized from acetonitrile (3 mL) and water(1 mL) to yield(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N-(4-methoxybenzyl)-3-methyl-7,9-12-14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(15 mg, 11%) as a mixture of diastereomers and as a red-brown solid: ¹HNMR (500 MHz, CD₃OD) δ 8.07 (s, 0.3H), 8.05 (s, 0.7H), 7.21 (d, J=8.5Hz, 1H), 7.16 (d, J=8.0 Hz, 0.3H), 7.11 (d, J=8.0 Hz, 0.7H), 6.87 (d,J=8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 0.3H), 6.73 (d, J=8.0 Hz, 0.7H), 5.80(s, 1H), 6.12 (s, 0.3H), 5.93 (s, 0.7H), 4.93-4.87 (m, 2H), 4.37 (s,2H), 4.35-4.28 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.70 (s, 2H), 3.58(s, 2H), 3.53 (d, J=10.5 Hz, 2H), 3.45-3.39 (m, 2H), 3.23 (d, J=18.5 Hz,1H), 3.10-3.02 (m, 1H), 2.17 (s, 1.4H), 2.16 (s, 0.6H), 1.27 (d, J=6.0Hz, 2.1H), 1.22 (d, J=6.0 Hz, 0.9H); MS (ESI+) m/z 803 (M+H); HPLC 98.5%(AUC), t_(R) 13.14 min.

Example 29 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamideHydrochloride

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (50 mg, 0.073 mmol) in THF (5 mL) were added 3-aminopyridine (14mg, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). Thereaction mixture was stirred at room temperature under nitrogen for 12h. The reaction was quenched by adding 1 N HCl solution (5 mL) and brine(25 mL). The aqueous layer was extracted with methylene chloride (2×50mL). The organic layer was separated, dried (MgSO₄), filtered andconcentrated to give the crude product. The crude material was purifiedby preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) andlyophilized to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(5 mg, 9%) as a dark red solid. To a solution of this material inanhydrous methanol at 0° C. was added 1.25 N HCl in methanol (8 μL,0.008 mmol) and the mixture was stirred at 0° C. for 30 min. Thereaction mixture was concentrated, triturated with diethyl ether, andlyophilized from acetonitrile/water to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-N-(pyridin-3-yl)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamidehydrochloride (5 mg, 95%) as a red-brown powder and as a mixture ofdiastereomers: ¹H NMR (500 MHz, CD₃OD) δ 9.43 (s, 1H), 8.55 (d, J=5.0Hz, 1H), 8.43 (t, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.99 (t, J=16.5 Hz, 1H),6.70 (s, 1H), 6.17 (s, 0.4H), 6.02 (s, 0.6H), 4.94-4.83 (m, 2H), 3.72(s, 3H), 3.67 (t, J=3.5 Hz, 1H), 3.63-3.60 (m, 1H), 3.57 (s, 3H), 3.51(d, J=19.5 Hz, 3H), 3.47-3.37 (m, 2H), 3.26 (d, J=19.0 Hz, 1H),3.09-2.99 (m, 1H), 2.25 (s, 3H), 1.26 (d, J=6.0 Hz, 1.8H), 1.22 (d,J=6.0 Hz, 1.2H); MS (ESI+) m/z 760 (M+H); HPLC 90.8% (AUC), t_(R) 11.81min

Example 30 Preparation of(6R,6aS,14aR)—N-Benzyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (50 mg, 0.073 mmol) in THF (5 mL) was added benzyl amine (15 μL,0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g),and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reactionmixture was stirred at room temperature under nitrogen for 12 h. Thereaction was quenched by adding 1 N HCl solution (5 mL) and brine (25mL). The aqueous layer was extracted with methylene chloride (2×50 mL).The organic layer was separated, dried (MgSO₄), filtered andconcentrated to give the crude product. The crude material was purifiedby preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) andlyophilized to afford(6R,6aS,14aR)—N-benzyl-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(19 mg, 33%) as a red-brown powder and as a mixture of diastereomers: ¹HNMR (500 MHz, CD₃OD) δ 8.12 (s, 1H), 7.32-7.21 (m, 5H), 6.61 (s, 1H),5.99 (s, 1H), 4.96-4.87 (m, 2H), 4.53-4.33 (m, 2H), 3.75 (s, 3H),3.75-3.72 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H), 3.47-3.38 (m, 4H), 3.25(d, J=18.7 Hz, 1H), 3.06 (t, J=9.5 Hz, 1H), 2.19 (s, 3H), 1.27 (d, J=6.5Hz, 3H); MS (ESI−) m/z 771 (M−H); HPLC>99% (AUC), t_(R) 13.83 min.

Example 31 Preparation of(6R,6aS,14aR)-1,6,8,14a-Tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-isopropyl-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (50 mg, 0.073 mmol) in THF (5 mL) was added 2-methylethylamine (12μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). Thereaction mixture was stirred at room temperature under nitrogen for 12h. The reaction was quenched by adding 1 N HCl solution (5 mL) and brine(25 mL). The aqueous layer was extracted with methylene chloride (2×50mL). The organic layer was separated, dried (MgSO₄), filtered andconcentrated to give the crude product. The crude material was purifiedby preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) andlyophilized to afford(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-isopropyl-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(8 mg, 15%) as a red-brown powder and as a mixture of diastereomers: ¹HNMR (500 MHz, CD₃OD) δ 8.11 (s, 1H) 6.59 (s, 1H), 6.19 (s, 0.2H), 5.95(s, 0.8H), 4.97-4.89 (m, 2H), 4.10-4.03 (m, 1H), 3.75 (s, 3H), 3.73-3.69(m, 1H), 3.64 (s, 2H), 3.59 (s, 3H), 3.57 (d, J=16.0 Hz, 3H), 3.47-3.35(m, 1H), 3.23 (d, J=18.7 Hz, 1H), 3.09-3.02 (m, 1H), 2.22 (s, 3H), 1.27(d, J=6.0 Hz, 2.4H), 1.23 (d, J=6.0 Hz, 0.6H), 1.14 (d, J=17.5 Hz, 6H);MS (ESI−) m/z 723 (M−H); HPLC>99% (AUC), t_(R) 12.93 min.

Example 32 Preparation of Benzyl2-46R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamido)acetate

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (50 mg, 0.073 mmol) in THF (5 mL) was added benzyl2-(methylamino)acetate (30 mg, 0.15 mmol), polystyrene carbodiimide (130mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg,0.15 mmol). The reaction mixture was stirred at room temperature undernitrogen for 12 h. The reaction was quenched by adding 1 N HCl solution(5 mL) and brine (25 mL). The aqueous layer was extracted with methylenechloride (2×50 mL). The organic layer was separated, dried (MgSO₄),filtered and concentrated to give the crude product. The crude materialwas purified by preparative HPLC (10:90 acetonitrile/water to 60:40acetonitrile/water with 0.05% TFA over 10 min, then isocratic) andlyophilized to afford benzyl2-((6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,3-dimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamido)acetate(17 mg, 23%) as a red-brown powder and as a mixture of diastereomers: ¹HNMR (500 MHz, CDCl₃) δ 14.18 (s, 1H), 8.18 (s, 1H), 7.50-7.31 (m, 5H),6.82 (d, J=8.0 Hz, 1H), 6.59 (s, 1H), 6.20 (s, 1H), 5.88 (s, 1H),5.39-5.06 (m, 3H), 4.97-4.88 (m, 1H), 4.82-4.52 (m, 2H), 3.78 (s, 2H),3.74 (s, 3H), 3.74-3.67 (m, 2H), 3.60 (s, 3H), 3.59-3.52 (m, 3H), 3.42(s, 3H), 3.39-3.28 (m, 2H), 3.18-3.03 (m, 1H), 2.91 (s, 3H), 2.15 (s,3H), 1.35 (d, J=6.5 Hz, 2H); MS (APCI−) m/z 843 (M−H); HPLC 97.2% (AUC),t_(R) 12.84 min.

Example 33 Preparation of (6R,6aS,14aR)-3-Phenylpropyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (24 mg, 0.035 mmol) in acetone (3 mL) were added potassiumcarbonate (17 mg, 0.12 mmol), 3-phenylpropyl bromide (29 mg, 0.15 mmol)and a catalytic amount of potassium iodide (4 crystals), and then thereaction was heated to 70° C. under nitrogen. After 1.5 days, thereaction mixture was concentrated under reduced pressure. The crudeproduct was purified by preparative TLC (silica gel, 95:5chloroform/methanol) and then by semi-preparative HPLC (20:80acetonitrile/water to 100% acetonitrile with 0.05% TFA over 40 min) Theresulting product was lyophilized from acetonitrile (3 mL) and water (1mL) to yield (6R,6aS,14aR)-3-phenylpropyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(3.8 mg, 14%) as a red-orange solid: ¹H NMR (500 MHz, CDCl₃) δ 14.18 (s,1H), 12.18 (s, 1H), 8.21 (s, 1H), 7.28-7.25 (m, 2H), 7.19-7.16 (m, 1H),7.14-7.12 (d, J=7.5 Hz, 2H), 6.85 (d, J=9.0 Hz, 1H), 6.55 (s, 1H), 5.87(s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 1H), 4.31-4.22 (m,2H), 3.80 (s, 3H), 3.73-3.71 (dd, J=9.5, 3.0 Hz, 1H), 3.69 (s, 1H), 3.60(s, 3H), 3.57 (dd, J=20.0, 6.5 Hz, 2H), 3.41 (s, 3H), 3.36-3.34 (m, 3H),3.13 (t, J=9.5 Hz, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.06-2.00(m, 3H), 1.35 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 802 (M+H); HPLC 98.8%(AUC), t_(R) 16.81 min

Example 34 Preparation of (6R,6aS,14aR)-Ethyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (21 mg, 0.089 mmol) in methylene chloride (0.2 mL) at 0° C. wereadded polystyrene carbodiimide (45 mg, 0.050 mmol), absolute ethanol (1mL) and a catalytic amount of 4-pyrrolidinopyridine (1 drop), and thenthe reaction was heated to 40° C. under nitrogen. After 4 h, thereaction mixture was filtered and concentrated under reduced pressure.The crude product was purified by preparative TLC (silica gel, 90:10chloroform/methanol). The resulting product was lyophilized fromacetonitrile (3 mL) and water (1 mL) to yield (6R,6aS,14aR)-ethyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(3.6 mg, 16%) as an orange solid: ¹H NMR (500 MHz, CDCl₃) δ 14.17 (s,1H), 12.18 (s, 1H), 8.21 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.53 (s, 1H),5.87 (s, 1H), 5.20 (s, 1H), 4.96 (t, J=9.0 Hz, 1H), 4.67-4.65 (m, 2H),4.37-4.25 (m, 2H), 3.79 (s, 3H), 3.73-3.71 (m, 2H), 3.61 (s, 3H), 3.57(dd, J=19.5, 7.0 Hz, 1H), 3.40 (s, 3H), 3.37-3.32 (m, 2H), 3.13 (t,J=9.5 Hz, 2H), 2.42 (s, 3H), 1.37-1.32 (m, 6H); MS (ESI+) m/z 712 (M+H);HPLC 99.0% (AUC), t_(R) 14.11 min.

Example 35 Preparation of (6R,6aS,14aR)-2-Morpholinoethyl1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (27 mg, 0.039 mmol) in methylene chloride (3 mL) at 0° C. wereadded polystyrene carbodiimide (57 mg, 0.063 mmol), 2-morpholinoethanol(0.3 mL, 2.5 mmol) and a catalytic amount of 4-pyrrolidinopyridine (1drop) and then the reaction was heated to 40° C. under nitrogen. After18 h, the reaction was filtered and concentrated under reduced pressure.The crude product was purified by preparative HPLC (10:90acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10min, then isocratic). The resulting product was lyophilized fromacetonitrile (3 mL) and water (1 mL) to yield(6R,6aS,14aR)-2-morpholinoethyl1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(2.2 mg, 7.1%) as a mixture of diastereomers and as an orange solid: ¹HNMR (500 MHz, CDCl₃) δ 14.21 (s, 1H), 8.18 (s, 1H), 6.84 (d, J=8.0 Hz,0.8H), 6.54 (s, 1H), 6.22 (s, 0.2H), 6.18 (s, 0.2H), 5.87 (s, 0.8H),5.22 (s, 1H), 4.96 (s, 1H), 4.67 (d, J=8.0 Hz, 2H), 3.79 (s, 3H),3.73-3.70 (m, 2H), 3.60 (s, 3H), 3.58-3.49 (m, 5H), 3.40 (s, 3H),3.36-3.32 (m, 2H), 3.13 (t, J=9.0 Hz, 1H), 2.48-2.47 (m, 2H), 2.38 (s,3H), 1.35 (d, J=6.5 Hz, 3H), 1.33-1.25 (m, 7H); MS (ESI+) m/z 797 (M+H);HPLC 96.5% (AUC), t_(R) 9.36 min.

Example 36 Preparation of (6R,6aS,14aR)-Isobutyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid² (37 mg, 0.055 mmol) in methylene chloride (3 mL) at 0° C. wereadded polystyrene carbodiimide (74 mg, 0.083 mmol), 2-methyl propanol (1mL, 10 mmol) and a catalytic amount of 4-pyrrolidinopyridine (2 drops)and the reaction was allowed to warm to room temperature under nitrogen.After 18 h, the reaction mixture was filtered and concentrated underreduced pressure. The crude product was purified by preparative TLC(silica gel, 90:10 chloroform/methanol). The resulting product waslyophilized from acetonitrile (3 mL) and water (1 mL) to yield(6R,6aS,14aR)-isobutyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide(11 mg, 26%) as an orange solid: ¹H NMR (500 MHz, CDCl₃) δ 14.17 (s,1H), 12.26 (s, 1H), 8.21 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.53 (s, 1H),5.87 (s, 1H), 5.21 (s, 1H), 4.96 (s, 1H), 4.68-4.67 (m, 2H), 4.11-4.08(m, 1H), 4.00-3.98 (m, 1H), 3.79 (s, 3H), 3.72 (dd, J=9.5, 3.5 Hz, 1H),3.69-3.68 (m, 1H), 3.61 (s, 3H), 3.58-3.56 (m, 2H), 3.41 (s, 3H),3.36-3.32 (m, 2H), 3.13 (t, J=9.5 Hz, 1H), 2.44 (s, 3H), 2.05-1.97 (m,1H), 1.35 (d, J=6.5 Hz, 3H), 0.97-0.95 (m, 6H); MS (ESI+) m/z 740 (M+H);HPLC 94.1% (AUC), t_(R) 15.88 min

Example 37 Preparation of (6R,6aS,14aR)-Benzyl1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of(6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylicacid (80 mg, 0.12 mmol) in THF (1 mL) was added polystyrene-carbodiimide(208 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (32 mg, 0.24 mmol)and benzyl alcohol (0.5 mL). The reaction mixture was stirred at roomtemperature under nitrogen for 17 h. The reaction was filtered through amicro filter and concentrated. The crude material was purified bypreparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/waterwith 0.05% TFA over 10 min, then isocratic) to afford(6R,6aS,14aR)-benzyl1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateas a mixture of diastereomers (14 mg, 20%) and as a dark red solid: ¹HNMR (500 MHz, CDCl₃) δ 14.26 (s, 0.3H), 14.17 (s, 0.7H), 12.09 (s,0.3H), 12.08 (s, 0.7H), 8.32 (br s, 6H), 8.27 (s, 0.3H), 8.21 (s, 0.7H),6.86 (d, J=8.0 Hz, 1H), 6.52 (s, 1H), 5.87 (s, 0.7H), 5.86 (s, 0.3H),5.28 (s, 2H), 4.96 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 3.80 (s,3H), 3.74-3.70 (m, 2H), 3.61 (s, 3H), 3.58-3.53 (m, 2H), 3.40 (s, 3H),3.37-3.30 (m, 3H), 3.13 (t, J=9.0 Hz, 1H), 2.41 (s, 2H), 3.39 (s, 1H),1.36 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 774 (M+H); HPLC>99% (AUC), t_(R)15.52 min.

Example 38 Preparation of (6R,6aS,14aR)-Methyl4-bromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(50 mg, 0.072 mmol) in chloroform (1 mL) was added N-bromosuccinimide(13 mg, 0.072 mmol) followed by benzoyl peroxide (1-2 mg). The reactionmixture was refluxed at 75° C. for 1 h. After cooled to roomtemperature, the reaction mixture was diluted with chloroform (10 mL)and washed with saturated sodium bicarbonate (5 mL). The aqueous layerwas further extracted with chloroform (2×10 mL). The combined organicswere dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by preparative TLC (silica gel, 95:5 chloroform/methanol) andsemi-preparative HPLC to afford (6R,6aS,14aR)-methyl4-bromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(20 mg, 36%) as a dark red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.22 (s,1H), 11.62 (br s, 1H), 8.19 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.88 (s,1H), 5.29 (s, 1H), 4.99 (s, 1H), 4.72 (s, 1H), 4.68 (d, J=8.5 Hz, 1H),3.88 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.55 (d,J=6.5 Hz, 1H), 3.45 (d, J=20.5 Hz, 1H), 3.41 (s, 3H), 3.38-3.31 (m, 1H),3.13 (t, J=9.5 Hz, 1H), 2.59 (s, 3H), 2.48 (d, J=4.5 Hz, 1H), 1.36 (d,J=6.0 Hz, 3H); MS (ESI+) m/z 776 (M+H); HPLC>99% (AUC), t_(R) 14.64 min.

Example 39 Preparation of (6R,6aS,14aR)-Methyl4,10-dibromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(50 mg, 0.072 mmol) in chloroform (1 mL) was added N-bromosuccinimide(26 mg, 0.14 mmol) followed by benzoyl peroxide (1-2 mg). The reactionmixture was refluxed at 75° C. for 50 min. After cooled to roomtemperature, the reaction mixture was diluted with chloroform (10 mL)and washed with saturated sodium bicarbonate (5 mL). The aqueous layerwas further extracted with chloroform (2×10 mL). The combined organicswere dried (Na₂SO₄), filtered and concentrated. The crude material waspurified by preparative TLC (silica gel, 95:5 chloroform/methanol) andsemi-preparative HPLC to afford (6R,6aS,14aR)-methyl4,10-dibromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(26 mg, 41%) as a brown-red solid: ¹H NMR (500 MHz, CDCl₃) δ 13.78 (brs, 1H), 11.66 (br s, 1H), 8.19 (s, 1H), 7.11 (br s, 1H), 5.81 (d, J=9.0Hz, 1H), 5.27 (s, 1H), 4.99 (s, 1H), 4.72 (s, 1H), 3.88 (s, 3H), 3.82(s, 3H), 3.77-3.73 (m, 2H), 3.60 (s, 3H), 3.59-3.53 (m, 2H), 3.45 (d,J=20.5 Hz, 1H), 3.41 (s, 3H), 3.11 (t, J=9.0 Hz, 1H), 2.59 (s, 3H), 2.46(d, J=4.0 Hz, 1H), 1.33 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 854 (M+H); HPLC91.1% (AUC), t_(R) 16.86 min.

Example 40 Preparation of (6R,6aS,14aR)-Methyl10-chloro-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateand (6R,6aS,14aR)-Methyl4,10-dichloro-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in chloroform (2 mL) was added N-chlorosuccinimide(28 mg, 0.21 mmol) followed by benzoyl peroxide (1-2 mg). The reactionmixture was refluxed at 75° C. for 12 h, and then N-chlorosuccinimide(19 mg, 0.14 mmol) was refilled and the reaction mixture was refluxedfor another 5 h. After cooled to room temperature, the reaction mixturewas diluted with chloroform (10 mL) and washed with saturated sodiumbicarbonate (5 mL). The aqueous layer was further extracted withchloroform (2×10 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude material was purified bypreparative TLC (silica gel, 95:5 chloroform/methanol) andsemi-preparative HPLC to afford (6R,6aS,14aR)-methyl10-chloro-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(13.3 mg, 14%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 13.72 (s, 1H),12.11 (s, 1H), 8.22 (s, 1H), 7.11 (br s, 1H), 6.54 (s, 1H), 5.73 (s,1H), 5.20 (s, 1H), 4.95 (s, 1H), 4.60 (s, 1H), 3.85 (s, 3H), 3.82 (s,3H), 3.73 (s, 2H), 3.60 (s, 3H), 3.59-3.52 (m, 1H), 3.41 (s, 3H),3.38-3.31 (m, 1H), 3.34 (d, J=19.5 Hz, 1H), 3.11 (t, J=9.5 Hz, 1H), 2.48(br s, 1H), 2.41 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 732(M+H); HPLC 95.1% (AUC), t_(R) 14.34 min; and (6R,6aS,14aR)-methyl4,10-dichloro-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(3.6 mg, 3%) as a dark blue solid: ¹H NMR (500 MHz, CDCl₃) δ 13.72 (s,1H), 11.70 (br s, 1H), 8.20 (s, 1H), 7.11 (br s, 1H), 5.71 (s, 1H), 5.26(s, 1H), 5.00 (s, 1H), 4.71 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.73(s, 2H), 3.60 (s, 3H), 3.59-3.52 (m, 1H), 3.50-3.41 (m, 2H), 3.41 (s,3H), 3.11 (t, J=9.0 Hz, 1H), 2.54 (s, 3H), 2.46 (s, 1H), 1.34 (d, J=6.0Hz, 3H); MS (ESI+) m/z 766 (M+H); HPLC 92.8% (AUC), t_(R) 15.63 min

Example 41 Preparation of (6R,6aS,14aR)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in acetonitrile (1 mL) was added zirconyl(IV)nitrate hydrate (36 mg, 0.16 mmol). The reaction mixture was heated to70° C. for 1 h. After cooled to room temperature, the reaction mixturewas filtered through a micro filter and the filtrate was concentratedunder reduced pressure. The crude material was purified by preparativeTLC (silica gel, 96:4 chloroform/methanol) and semi-preparative HPLC toafford (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(34 mg, 33%) as a dark red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.23 (s,1H), 12.27 (br s, 1H), 8.19 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.89 (s,1H), 5.31 (s, 1H), 5.19 (s, 1H), 4.69 (d, J=8.5 Hz, 1H), 4.61 (s, 1H),3.91 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.49 (dd,J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.35 (m, 1H), 3.28 (d, J=19.5Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.40 (s, 3H),1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 743 (M+H); HPLC 98.0% (AUC), t_(R)13.79 min

Example 42 Preparation of (6R,6aS,14aR)-Methyl4-amino-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate2,2,2-trifluoroacetate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-(4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(105 mg, 0.140 mmol) in ethanol (2 mL) and THF (2 mL) was addedpalladium on carbon (10%, 30 mg), then the reaction mixture was shakedunder a hydrogen atmosphere at 45 psi at ambient temperature for 12 h.The reaction mixture was filtered through diatomaceous earth and the padwas rinsed with chloroform. The filtrate was concentrated under reducedpressure. The crude material was purified by semi-preparative HPLC(20:80 acetonitrile/water to 100% acetonitrile with 0.05% TFA over 40min) to afford (6R,6aS,14aR)-methyl4-amino-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate2,2,2-trifluoroacetate (10 mg, 10%) as a red-brown solid: ¹H NMR (500MHz, CDCl₃) δ 14.20 (s, 1H), 10.76 (br s, 1H), 8.20 (s, 1H), 6.85 (d,J=9.0 Hz, 1H), 5.87 (s, 1H), 5.06 (d, J=6.5 Hz, 1H), 4.67 (d, J=8.0 Hz,1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.74-3.68 (m, 3H), 3.61 (s, 3H), 3.42(s, 3H), 3.38-3.25 (m, 3H), 3.15-3.08 (m, 2H), 2.27 (s, 3H), 1.36 (d,J=6.0 Hz, 3H); MS (ESI+) m/z 713 (M+H); HPLC 96.5% (AUC), t_(R) 12.03min

Example 43 Preparation of (6R,6aS,14aR)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.143 mmol) in methanol (2 mL) was added 29.5% NH₄OH (0.1 mL)at room temperature, and the mixture was stirred under nitrogen for 2 h.29.5% NH₄OH (0.1 mL) was refilled and the mixture was stirred for 3 h.The reaction mixture was quenched with a saturated solution of ammoniumchloride and extracted with chloroform. The combined extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by preparative TLC (silica gel, 90:10chloroform/methanol) to afford (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(52 mg, 52%) as a blue solid: ¹H NMR (500 MHz, CDCl₃) δ 15.80 (br s,1H), 11.97 (s, 1H), 8.20 (br s, 1H), 7.90 (s, 1H), 6.90 (d, J=9.0 Hz,1H), 6.49 (s, 1H), 5.27 (s, 1H), 5.00 (br s, 1H), 4.76 (br s, 1H), 4.70(d, J=9.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.75-3.67 (m, 2H), 3.60(s, 3H), 3.58-3.54 (m, 2H), 3.40 (s, 3H), 3.32-3.28 (m, 2H), 3.12 (t,J=9.5 Hz, 1H), 2.54 (br s, 1H), 2.36 (s, 3H), 1.34 (d, J=5.5 Hz, 3H); MS(ESI+) m/z 697 (M+H); HPLC 96.6% (AUC), t_(R) 10.34 min.

Example 44 Preparation of (6R,6aS,14aR,E)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-9-(methylimino)-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.143 mmol) in methanol (2 mL) was added methylamine (40% inwater, 0.1 mL) at room temperature, and the mixture was stirred undernitrogen for 1 h. The reaction mixture was quenched with a saturatedsolution of ammonium chloride and extracted with chloroform. Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preparative TLC (silica gel,90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-9-(methylimino)-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(30 mg, 29%) as a blue solid: ¹H NMR (500 MHz, CDCl₃) δ 11.94 (s, 1H),7.88 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 5.91 (s, 1H), 5.26(s, 1H), 5.00 (dd, J=10.0, 6.0 Hz, 1H), 4.75-4.72 (m, 2H), 3.82 (s, 3H),3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.61 (s, 3H), 3.57 (dd, J=19.5, 6.5 Hz,1H), 3.40 (s, 3H), 3.39-3.36 (m, 1H), 3.34 (d, J=4.5 Hz, 3H), 3.29 (d,J=19.5 Hz, 1H), 3.15 (t, J=9.5 Hz, 1H), 2.52 (d, J=4.5 Hz, 1H), 2.36 (s,3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 711 (M+H); HPLC 93.4% (AUC),t_(R) 10.83 min.

Example 45 Preparation of (6R,6aS,14aR,E)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(hydroxyimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.143 mmol) in methanol (1 mL) and pyridine (1 mL) was addedhydroxylamine hydrochloride (100 mg, 1.43 mmol) at room temperature, andthe mixture was stirred under nitrogen overnight. The mixture wasdiluted with ethyl acetate, washed with 1 N HCl and brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified bypreparative TLC (silica gel, 95:5 chloroform/methanol) to afford(6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(hydroxyimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(17 mg, 16%) as an orange solid: ¹H NMR (500 MHz, CDCl₃) δ 12.02 (s,1H), 8.45 (s, 1H), 6.93 (s, 1H), 6.54 (s, 1H), 6.52 (d, J=9.0 Hz, 1H),5.33 (br s, 1H), 5.00 (br s, 1H), 4.84-4.82 (m, 2H), 3.83 (s, 3H), 3.80(s, 3H), 3.78-3.68 (m, 3H), 3.62 (s, 3H), 3.54 (dd, J=19.5, 6.5 Hz, 1H),3.45-3.42 (m, 1H), 3.43 (s, 3H), 3.36 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5Hz, 1H), 2.46 (d, J=5.0 Hz, 1H), 2.39 (s, 3H), 1.38 (d, J=6.0 Hz, 3H);MS (ESI+) m/z 713 (M+H); HPLC 95.0% (AUC), t_(R) 12.31 min.

Example 46 Preparation of (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(2-methoxyethylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in methanol (3 mL) was added 2-methoxyethanamine(107 mg, 1.43 mmol). The reaction mixture was stirred at roomtemperature under nitrogen for 3 h. The reaction was quenched by addingsaturated ammonium chloride solution (15 mL). Then it was extracted withchloroform (75 mL) and washed with water (2×25 mL). The organic layerwas separated, dried (MgSO₄), filtered and concentrated to give thecrude product. The crude material was purified by preparative TLC(silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(2-methoxyethylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(33.8 mg, 31.2%) as a dark blue solid: ¹H NMR (500 MHz, CDCl₃) δ 11.95(s, 1H), 7.93 (s, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.49 (s, 1H), 6.05 (s,1H), 5.27 (s, 1H), 4.99 (t, J=8.0 Hz, 1H), 4.74-4.69 (m, 2H), 3.83 (s,4H), 3.79 (s, 4H), 3.72-3.69 (m, 4H), 3.65-3.59 (m, 4H), 3.57-3.55 (m,1H), 3.40 (s, 3H), 3.37 (s, 3H), 3.14 (t, J=9.1 Hz, 1H), 2.48 (d, J=3.8Hz, 1H), 2.37 (s, 3H), 1.58 (br s, 1H), 1.37 (d, J=6.1 Hz, 3H); MS(ESI+) m/z 755 (M+H); HPLC 88.9% (AUC), t_(R)=11.14 min

Example 47 Preparation of (6R,6aS,14aR,E)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(3-methoxypropylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in methanol (3 mL) was added 3-methoxypropan-1-amine(127 mg, 1.43 mmol). The reaction mixture was stirred at roomtemperature under nitrogen for 2 h. The reaction was quenched by addingsaturated ammonium chloride solution (25 mL). Then it was extracted withchloroform (75 mL) and washed with water (2×25 mL). The organic layerwas separated, dried (MgSO₄), filtered and concentrated to give thecrude product. The crude material was purified by preparative TLC(silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(3-methoxypropylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(53.3 mg, 48.3%) as a dark blue solid: ¹H NMR (500 MHz, CDCl₃) δ 11.95(s, 1H), 7.90 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (s, 1H), 6.04 (s,1H), 5.27 (s, 1H), 5.01-4.98 (m, 1H), 4.73 (d, J=8.6 Hz, 2H), 3.83 (s,3H), 3.79 (s, 3H), 3.75-3.72 (m, 3H), 3.69-3.68 (m, 1H), 3.62 (s, 4H),3.46 (t, J=6.1 Hz, 2H), 3.40 (s, 3H), 3.32 (s, 4H), 3.28 (s, 1H), 3.14(t, J=9.2 Hz, 1H), 2.48 (d, J=4.9 Hz, 1H), 2.37 (s, 3H), 2.07-2.00 (m,2H), 1.37 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 769 (M+H); HPLC 89.1% (AUC),t_(R)=11.35 min.

Example 48 Preparation of (6R,6aS,14aR,E)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(3-hydroxypropylimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in methanol (3 mL) was added 3-aminopropan-1-ol (107mg, 1.43 mmol). The reaction mixture was stirred at room temperatureunder nitrogen for 2 h. The reaction was quenched by adding saturatedammonium chloride solution (25 mL). Then it was extracted withchloroform (75 mL) and washed with water (2×25 mL). The organic layerwas separated, dried (MgSO₄), filtered and concentrated to give thecrude product. The crude material was purified by preparative TLC(silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(3-hydroxypropylimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(61.3 mg, 56.6%) as a dark blue solid: ¹H NMR (500 MHz, CDCl₃) δ 11.94(s, 1H), 7.89 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.48 (s, 1H), 6.12 (s,1H), 5.27 (s, 1H), 5.02-4.99 (m, 1H), 4.74 (d, J=9.5 Hz, 2H), 4.12 (dd,J=14.2, 7.1 Hz, 2H), 3.83 (s, 3H), 3.81-3.72 (m, 9H), 3.68 (br s, 1H),3.60 (s, 3H), 3.40 (s, 4H), 3.13 (t, J=9.1 Hz, 1H), 2.53 (s, 1H), 2.36(s, 3H), 2.02-2.00 (m, 2H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 755(M+H); HPLC 97.5% (AUC), t_(R)=10.36 min.

Example 49 Preparation of (6R,6aS,14aR)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Isomer A] and (6R,6aS,14aR)-Methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Isomer B]

Step A: To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.143 mmol) in methylene chloride (2 mL) was added Dess-Martinperiodinane (73 mg, 0.17 mmol) at room temperature, and the mixture wasstirred under nitrogen for 3 h. The reaction mixture was quenched with asaturated solution of sodium bicarbonate and extracted with ethylacetate. The combined extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated to afford a ketone (83 mg, 83%) as a redsolid: ¹H NMR (500 MHz, CDCl₃) δ 14.05 (s, 1H), 12.10 (s, 1H), 8.22 (s,1H), 6.99 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.89 (s, 1H), 5.20 (s, 1H),4.96 (t, J=8.0 Hz, 1H), 4.81 (dd, J=8.0, 1.5 Hz, 1H), 4.66 (d, J=10.0Hz, 1H), 3.90 (d, J=10.0 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J=1.5 Hz, 1H),3.61-3.52 (m, 2H), 3.55 (s, 3H), 3.53 (s, 3H), 3.41 (s, 3H), 3.34 (d,J=19.5 Hz, 1H), 2.40 (s, 3H), 1.46 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 696(M+H).

Step B: To a solution of the ketone from Step A (83 mg, 0.12 mmol) inmethanol (1 mL) was added hydroxylamine hydrochloride (83 mg, 1.2 mmol)and pyridine (0.1 mL) at room temperature. The mixture was stirred undernitrogen for 4 h. The reaction mixture was quenched with 1 N HCl andextracted with ethyl acetate. The combined extracts were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by preparative TLC (silica gel, 95:5 chloroform/methanol) toafford (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,65)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(isomer A, 24 mg, 28%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.10(s, 1H), 12.09 (s, 1H), 8.24 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.54 (s,1H), 6.16 (s, 1H), 5.62 (t, J=8.0 Hz, 1H), 5.20 (s, 1H), 4.98 (d, J=7.0Hz, 1H), 4.96 (dd, J=10.0, 7.0 Hz, 1H), 4.76-4.72 (m, 1H), 4.65 (d,J=10.0 Hz, 1H), 4.06 (d, J=7.0 Hz, 1H), 3.84 (s, 3H), 3.61 (s, 3H), 3.58(dd, J=19.5, 6.5 Hz, 1H), 3.47 (s, 3H), 3.41 (s, 3H), 3.34 (d, J=19.5Hz, 1H), 2.40 (s, 3H), 2.31 (d, J=3.0 Hz, 1H), 1.21 (d, J=6.0 Hz, 3H);MS (ESI+) m/z 711 (M+H); HPLC 93.1% (AUC), t_(R) 14.01 min; and(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,65)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(isomer B, 22 mg, 26%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.10(s, 1H), 12.09 (s, 1H), 8.20 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.53 (s,1H), 6.10 (s, 1H), 5.59 (dd, J=7.5, 1.0 Hz, 1H), 5.23 (s, 1H), 4.96 (dd,J=10.0, 7.0 Hz, 1H), 4.88 (d, J=1.0 Hz, 1H), 4.66 (d, J=10.0 Hz, 1H),4.22-4.18 (m, 1H), 4.05 (d, J=7.0 Hz, 1H), 3.78 (s, 3H), 3.56 (dd,J=19.5, 6.5 Hz, 1H), 3.52 (s, 3H), 3.46 (s, 3H), 3.41 (s, 3H), 3.34 (d,J=19.5 Hz, 1H), 2.39 (s, 3H), 2.28 (d, J=3.0 Hz, 1H), 1.27 (d, J=6.0 Hz,3H); MS (ESI+) m/z 711 (M+H); HPLC 98.8% (AUC), t_(R) 14.16 min.

Example 50 Preparation of (6R,6aS,14aR)-Methyl11-02S,3R,5R,6S,Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of the ketone from Step A of the preparation of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,65)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Isomer A] (Example 48) (53 mg, 0.076 mmol) in methanol (1 mL) was addedmethoxylamine hydrochloride (6.4 mg, 0.076 mmol) and pyridine (0.1 mL)at room temperature. The mixture was stirred under nitrogen for 2 h. Thereaction mixture was quenched with 1 N HCl and extracted with ethylacetate. The combined extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by preparative TLC(silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR)-methyl11-((2S,3R,5R,6S,Z)-3,5-dimethoxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(30 mg, 54%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.15 (s, 1H),12.09 (s, 1H), 8.20 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.86(s, 1H), 5.21 (s, 1H), 4.98-4.94 (m, 2H), 4.67-4.64 (m, 2H), 3.97 (s,3H), 3.84 (s, 3H), 3.71 (d, J=9.5 Hz, 1H), 3.59 (s, 3H), 3.57-3.52 (m,2H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 2.40 (s, 3H),1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 725 (M+H); HPLC 95.9% (AUC), t_(R)17.05 min.

Example 51 Preparation of2-((Z)-((2S,3R,5R,6S)-3,5-Dimethoxy-2-methyl-6-46R,6aS,14aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino)-2H-pyran-4(3H,5H,6H)-ylidene)aminooxy)aceticacid

To a solution of the ketone from Step A of the preparation of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,65)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Isomer A] (Example 48) (53 mg, 0.076 mmol) in methanol (1 mL) was addedcarboxymethoxylamine hemihydrochloride (8.3 mg, 0.076 mmol) and pyridine(0.1 mL) at room temperature. The mixture was stirred under nitrogen for2 h. The reaction mixture was quenched with 1 N HCl and extracted withethyl acetate. The combined extracts were washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified bypreparative TLC (silica gel, 90:10 chloroform/methanol) to afford2-((Z)-((2S,3R,5R,65)-3,5-dimethoxy-2-methyl-6-((6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino)-2H-pyran-4(3H,5H,6H)-ylidene)aminooxy)aceticacid (40 mg, 68%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.18 (s,1H), 12.12 (s, 1H), 8.23 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.56 (s, 1H),5.91 (s, 1H), 5.24 (br s, 1H), 5.07 (d, J=1.5 Hz, 1H), 4.99 (d, J=6.5Hz, 1H), 4.82-4.74 (m, 3H), 4.70 (br s, 1H), 3.87 (s, 3H), 3.78 (d,J=9.5 Hz, 1H), 3.62-3.56 (m, 2H), 3.58 (s, 3H), 3.57 (s, 3H), 3.43 (s,3H), 3.37 (d, J=19.5 Hz, 1H), 2.43 (s, 3H), 1.41 (d, J=6.0 Hz, 3H); MS(ESI+) m/z 769 (M+H); HPLC 93.9% (AUC), t_(R) 14.32 min.

Example 52 Preparation of (6R,6aS,14aR)-Methyl11-02S,3R,5R,6S,Z)-4-(2-aminoethoxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of the ketone from Step A of the preparation of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Isomer A] (Example 48) (50 mg, 0.072 mmol) in methanol (1 mL) was added2-(aminooxy)-1-ethanaminum dihydrochloride (10.7 mg, 0.072 mmol) andpyridine (0.1 mL) at room temperature. The mixture was stirred undernitrogen for 6 h. The reaction mixture was quenched with a saturatedsolution of sodium bicarbonate and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preparative TLC (silica gel,90:10 chloroform/methanol) to afford (6R,6aS,14aR)-methyl11-((2S,3R,5R,6S,Z)-4-(2-aminoethoxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(18 mg, 33%) as a brown solid: ¹H NMR (500 MHz, CDCl₃) δ 8.20 (s, 1H),7.00 (br s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 4.98 (d, J=1.5 Hz, 1H),4.95 (d, J=6.0 Hz, 1H), 4.87 (br s, 1H), 4.29-4.26 (m, 3H), 3.83 (s,3H), 3.74-3.70 (m, 2H), 3.61-3.54 (m, 2H), 3.58 (s, 3H), 3.47 (s, 3H),3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 3.11-3.06 (m, 2H), 2.40 (s, 3H),1.37 (d, J=6.0 Hz, 3H), 1.24 (t, J=7.0 Hz, 2H); MS (ESI+) m/z 754 (M+H);HPLC 95.6% (AUC), t_(R) 10.86 min

Example 53 Preparation of (6aS,14aR,E)-Methyl1,8,14a-trihydroxy-6-(hydroxyimino)-11-((2S,3R,5R,6S,Z)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Step A: To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(200 mg, 0.287 mmol) in methylene chloride (4 mL) was added Dess-Martinperiodinane (365 mg, 0.86 mmol) at room temperature, and the mixture wasstirred under nitrogen for 2 h. The reaction mixture was quenched with asaturated solution of sodium bicarbonate and extracted with ethylacetate. The combined extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated to afford a diketone (120 mg, 60%) as a redsolid: ¹H NMR (500 MHz, CDCl₃) δ 14.04 (s, 1H), 12.10 (s, 1H), 8.31 (s,1H), 7.03 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 5.91 (s, 1H), 4.83 (d, J=8.0Hz, 1H), 3.96 (d, J=22.0 Hz, 1H), 3.91-3.50 (m, 4H), 3.86 (s, 3H), 3.85(d, J=22.0 Hz, 1H), 3.55 (s, 3H), 3.54 (s, 3H), 3.52 (s, 3H), 2.43 (s,3H), 1.45 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 694 (M+H).

Step B: To a solution of the diketone from Step A (112 mg, 0.162 mmol)in methanol (2 mL) was added hydroxylamine hydrochloride (23 mg, 0.33mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirredunder nitrogen for 4 h. The reaction mixture was quenched with 1 N HCland extracted with ethyl acetate. The combined extracts were washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by preparative TLC (silica gel, 90:10 chloroform/methanol) toafford (6aS,14aR,E)-methyl1,8,14a-trihydroxy-6-(hydroxyimino)-11-((2S,3R,5R,6S,Z)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(68 mg, 58%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.05 (s, 1H),12.04 (s, 1H), 8.32 (s, 1H), 7.60 (br s, 1H), 7.52 (br s, 1H), 7.04 (d,J=8.0 Hz, 1H), 6.61 (s, 1H), 5.88 (s, 1H), 5.05 (s, 1H), 4.75 (br s,1H), 4.70 (d, J=8.0 Hz, 1H), 4.36 (d, J=22.0 Hz, 1H), 3.84 (s, 3H), 3.83(d, J=22.0 Hz, 1H), 3.77-3.73 (m, 1H), 3.58 (s, 3H), 3.56-3.50 (m, 1H),3.52 (s, 3H), 3.46 (s, 3H), 2.41 (s, 3H), 1.40 (d, J=6.0 Hz, 3H); MS(ESI+) m/z 724 (M+H); HPLC 97.2% (AUC), t_(R) 13.52 min.

Example 54 Preparation of (6R,6aS,14aR)-Methyl11-((2S,3R,4R,5S,6S)-3,5-dimethoxy-6-methyl-4-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Step A: A mixture of(2R,3R,4S,5R)-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)-tetrahydro-2H-pyran-3,4,5-triyltriacetate (25 mg, 0.050 mmol), (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(35 mg, 0.050 mmol) and 4 Å molecular sieves (10 mg) in dichloromethane(1 mL) was stirred at room temperature under nitrogen for 1 h. Thenborontrifluoride diethyl etherate (3 μL, 0.02 mmol) was added at −42° C.The reaction mixture was stirred at −42° C. for 4 h, quenched withsodium bicarbonate (20 mg), filtered through diatomaceous earth andconcentrated. The crude product was purified by preparative TLC (95:5dichloromethane/methanol) and semi-preparative HPLC (45:55acetonitrile/water with 0.05% TFA) to afford(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((2S,3S,4R,5R,6S)-3,5-dimethoxy-2-methyl-6-((6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino)tetrahydro-2H-pyran-4-yloxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (17 mg, 32%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 14.20(s, 1H), 12.10 (s, 1H), 8.20 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.53 (s,1H), 5.85 (s, 1H), 5.23 (t, J=9.5 Hz, 1H), 5.22 (br s, 1H), 5.13 (t,J=9.7 Hz, 1H), 5.07 (dd, J=9.3, 8.2 Hz, 1H), 4.96 (d, J=6.4 Hz, 1H),4.84 (d, J=7.9 Hz, 1H), 4.66 (br s, 1H), 4.62 (d, J=8.8 Hz, 1H), 4.20(d, J=3.2 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.72-3.64 (m, 3H), 3.56(dd, J=19.7, 6.7 Hz, 1H), 3.50 (s, 3H), 3.40 (s, 3H), 3.33 (d, J=20.1Hz, 1H), 3.30-3.25 (m, 1H), 3.17 (t, J=9.3 Hz, 1H), 2.40 (s, 3H), 2.06(s, 3H), 2.04 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.33 (d, J=6.1 Hz,3H); MS (ESI+) m/z 1028 (M+H); HPLC 97.7% (AUC), t_(R) 19.30 min.

Step B: A mixture of(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((2S,3S,4R,5R,6S)-3,5-dimethoxy-2-methyl-6-((6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-6a-methoxy-2-(methoxycarbonyl)-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracen-11-ylamino)tetrahydro-2H-pyran-4-yloxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (44 mg, 0.043 mmol) and potassium carbonate (24 mg, 0.17mmol) in methanol (4 mL) was stirred at room temperature under nitrogenfor 4 h. The reaction mixture was concentrated under reduced pressure.The crude product was purified by semi-preparative HPLC (20:80acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 30min) to afford (6R,6aS,14aR)-methyl11-((2S,3R,4R,5S,6S)-3,5-dimethoxy-6-methyl-4-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(18 mg, 49%) as an orange-red solid: ¹H NMR (500 MHz, CD₃OD) δ 8.09 (s,1H), 6.61 (s, 1H), 5.94 (s, 1H), 4.92 (s, 1H), 4.52 (d, J=8.0 Hz, 1H),3.96-3.85 (m, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 3.65-3.61 (m, 2H), 3.60(s, 3H), 3.55-3.36 (m, 3H), 3.35 (s, 3H), 3.22-3.15 (m, 5H), 2.38 (s,3H), 1.25 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 860 (M+H); HPLC 97.6% (AUC),t_(R) 10.95 min.

Example 55 Preparation of (6R,6aS,14aR)-Methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3,12-dimethyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Diastereomer A] and [Diastereomer B]

To a −78° C. solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in THF (4 mL) was added a solution ofmethylmagnesium bromide in diethyl ether (3 M, 0.37 mL, 1.12 mmol)dropwise. The reaction mixture was stirred at −78° C. for 5 h, and thenquenched with a saturated solution of ammonium chloride. The mixture wasextracted with chloroform (3×20 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude was purified bypreparative TLC (silica gel, 95:5 chloroform/methanol), and then thediastereomers were separated by preparative HPLC (Chiralpak AD column,40:60 heptane/ethanol with 0.1% diethylamine) to afford(6R,6aS,14aR)-methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3,12-dimethyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer A, 39 mg, 39%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃)δ 15.20 (br s, 1H), 11.75 (br s, 1H), 7.82 (s, 1H), 6.78 (s, 1H), 6.53(s, 1H), 5.45 (s, 1H), 5.22 (s, 1H), 4.96 (s, 1H), 4.80-4.61 (m, 2H),3.81 (s, 3H), 3.76 (s, 3H), 3.71 (dd, J=9.0, 2.5 Hz, 1H), 3.64 (s, 1H),3.60 (s, 3H), 3.59-3.52 (m, 1H), 3.42 (s, 3H), 3.35-3.29 (m, 2H), 3.16(t, J=9.0 Hz, 1H), 2.95 (br s, 1H), 2.48 (br s, 1H), 2.38 (s, 3H), 1.79(s, 3H), 1.37 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 714 (M+H); HPLC>99%(AUC), t_(R) 11.18 min; and (6R,6aS,14aR)-methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3,12-dimethyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer B, 13 mg, 13%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃)δ 15.10 (br s, 1H), 12.02 (br s, 1H), 7.84 (s, 1H), 6.73 (d, J=8.5 Hz,1H), 6.54 (s, 1H), 5.48 (s, 1H), 5.25 (s, 1H), 4.98 (s, 1H), 4.78-4.63(m, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.72 (s, 2H), 3.59 (s, 5H), 3.38(s, 4H), 3.32 (d, J=19.0 Hz, 1H), 3.10 (t, J=9.0 Hz, 1H), 2.49 (br s,1H), 2.41 (s, 3H), 1.65 (s, 3H), 1.32 (d, J=6.0 Hz, 3H); MS (ESI+) m/z714 (M+H); HPLC 98.1% (AUC), t_(R) 11.45 min.

Example 56 Preparation of (6R,6aS,14aR)-Methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-12-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Diastereomer A] and [Diastereomer B]

To a −78° C. solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(50 mg, 0.072 mmol) in THF (2 mL) was added a solution ofphenylmagnesium bromide in THF (1 M, 0.72 mL, 0.72 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 3 h, and then quenched witha saturated solution of ammonium chloride. The mixture was extractedwith chloroform (3×15 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated. The crude was purified by preparative TLC(silica gel, 95:5 chloroform/methanol) twice to afford(6R,6aS,14aR)-methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-12-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer A, 8 mg, 14%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ15.16 (s, 1H), 11.96 (s, 1H), 7.62 (s, 1H), 7.56-7.53 (m, 2H), 7.37-7.29(m, 3H), 6.52 (s, 1H), 6.26 (d, J=8.5 Hz, 1H), 5.66 (s, 1H), 5.19 (s,1H), 4.94 (t, J=6.5 Hz, 1H), 4.70 (d, J=9.5 Hz, 1H), 4.64 (d, J=8.5 Hz,1H), 3.80 (s, 3H), 3.65 (s, 4H), 3.60-3.52 (m, 2H), 3.52 (s, 3H), 3.39(s, 3H), 3.35-3.13 (m, 3H), 3.00 (t, J=9.0 Hz, 1H), 2.48 (d, J=4.0 Hz,1H), 2.38 (s, 3H), 1.24 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 776 (M+H); HPLC97.5% (AUC), t_(R) 13.23 min; and (6R,6aS,14aR)-methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-12-phenyl-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer B, 5 mg, 9%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) δ15.07 (s, 1H), 11.58 (s, 1H), 7.51 (s, 1H), 7.37-7.35 (m, 2H), 7.28-7.24(m, 3H), 6.48 (s, 1H), 6.31 (d, J=9.0 Hz, 1H), 5.64 (s, 1H), 5.16 (s,1H), 4.95 (t, J=6.5 Hz, 1H), 4.70-4.62 (m, 2H), 3.81 (s, 3H), 3.56 (s,4H), 3.60-3.45 (m, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 3.35-3.17 (m, 3H),3.02 (t, J=9.0 Hz, 1H), 2.36 (s, 4H), 1.31 (d, J=6.0 Hz, 3H); MS (ESI+)m/z 776 (M+H); HPLC 93.7% (AUC), t_(R) 12.64 min

Example 57 Preparation of (6R,6aS,14aR)-Methyl12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[Diastereomer A] and [Diastereomer B]

To a −78° C. solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(100 mg, 0.14 mmol) in THF (4 mL) was added a solution of ethylmagnesiumbromide in THF (1 M, 1.12 mL, 1.12 mmol) dropwise. The reaction mixturewas stirred at −78° C. for 5 h, and then quenched with a saturatedsolution of ammonium chloride. The mixture was extracted with chloroform(3×20 mL). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude was purified by preparative TLC (silica gel,95:5 chloroform/methanol), and then the diastereomers were separated bypreparative HPLC (Chiralpak AD column, 40:60 heptane/ethanol with 0.1%diethylamine) to afford (6R,6aS,14aR)-methyl12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer A, 29 mg, 28%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃)δ 7.79 (s, 1H), 6.80 (br s, 1H), 6.51 (s, 1H), 5.52 (s, 1H), 4.98 (d,J=5.0 Hz, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78-3.62 (m,3H), 3.58 (s, 3H), 3.40 (s, 3H), 3.39-3.22 (m, 3H), 3.14 (t, J=9.0 Hz,1H), 2.80 (br s, 1H), 2.36 (s, 3H), 2.12-2.01 (m, 2H), 1.35 (d, J=6.0Hz, 3H), 0.72 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 728 (M+H); HPLC 98.1%(AUC), t_(R) 11.84 min; and (6R,6aS,14aR)-methyl12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(diastereomer B, 11 mg, 10%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃)δ 15.09 (s, 1H), 12.08 (br s, 1H), 7.75 (s, 1H), 6.75 (d, J=9.0 Hz, 1H),6.53 (s, 1H), 5.58 (s, 1H), 5.32 (s, 1H), 4.96 (s, 1H), 4.77 (d, J=8.0Hz, 1H), 4.76-4.62 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.72 (dd, J=9.5,3.0 Hz, 1H), 3.69 (s, 1H), 3.55 (s, 4H), 3.42 (s, 3H), 3.31 (d, J=19.0Hz, 1H), 3.12-3.00 (m, 3H), 2.70 (br s, 1H), 2.40 (s, 3H), 1.98-1.80 (m,2H), 1.31 (d, J=6.0 Hz, 3H), 0.57 (t, J=7.5 Hz, 3H); MS (ESI+) m/z 728(M+H); HPLC 98.3% (AUC), t_(R) 11.85 min

Example 58 Preparation of (6R,6aS,14aR)-Methyl12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(200 mg, 0.28 mmol) in THF (5 mL) was added 4-flourophenylmagnesiumbromide (4.30 mL, 1.0 M solution in THF, 4.30 mmol) at 30° C. Themixture was stirred under nitrogen for 30 min. The reaction mixture wasquenched with water (0.30 mL), the reaction was brought to roomtemperature and pH was adjusted to 7 with 1 N HCl. The reaction mixturewas extracted with dichloromethane (3×50 mL). The combined organic phasewas washed with brine, dried (Na₂SO₄), filtered and concentrated. Thecrude material was purified by preparative HPLC (10:90acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10min, then isocratic) to afford (6R,6aS,14aR)-methyl12-(4-fluorophenyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateas a diastereomer A (13 mg, 7%) and as a yellow solid: ¹H NMR (500 MHz,CD₃OD) δ 7.58-7.55 (m, 2H), 7.53 (s, 1H), 7.13-7.07 (m, 2H), 6.60 (s,1H), 5.69 (s, 1H), 4.93 (br s, 1H), 4.87 (s, 1H), 3.86 (s, 3H),3.69-3.66 (m, 1H), 3.65 (s, 3H), 3.58-3.46 (m, 5H), 3.37-3.33 (m, 2H),3.25-3.21 (m, 1H), 2.92 (t, J=9.0 Hz, 1H), 2.41 (s, 3H), 1.35-1.25 (m,2H), 1.17 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 794 (M+H); HPLC 95.4% (AUC),t_(R) 13.49 min.

Example 59 Preparation of (6R,6aS,14aR)-methyl12-(3-ethoxy-3-oxopropyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,14-dioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate[mixture of diastereomers]

To a −78° C. solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(50 mg, 0.072 mmol) in THF (2 mL) was added a solution of3-ethoxy-3-oxopropylzinc bromide in THF (0.5 M, 1.15 mL, 0.58 mmol)dropwise. The reaction mixture was stirred at −78° C. for 2 h, and thenquenched with a saturated solution of ammonium chloride. The mixture wasextracted with chloroform (3×10 mL). The combined organics were dried(Na₂SO₄), filtered and concentrated. The crude was purified bypreparative TLC (silica gel, 85:15 chloroform/methanol) to afford(6R,6aS,14aR)-methyl 1243-ethoxy-3-oxopropyl)-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,14-dioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(7 mg, 12%) as an orange solid and as a mixture of diastereomers: ¹H NMR(500 MHz, CD₃OD) δ 7.18 (s, 1H), 6.57 (s, 1H), 5.54 (s, 1H), 4.96 (s,1H), 4.88-4.83 (m, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.75-3.66 (m, 3H),3.57 (s, 3H), 3.34 (s, 3H), 3.25-3.16 (m, 2H), 3.03 (t, J=9.0 Hz, 1H),2.39 (s, 3H), 2.15-1.85 (m, 4H), 1.45-1.26 (m, 1H), 1.25 (d, J=5.5 Hz,3H), 1.09 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 799 (M+H); HPLC>99% (AUC),t_(R) 10.04 min.

Example 60 Preparation of(8aR,12R,12aS)-8a,12-Dihydroxy-5-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12a-methoxy-8a,9,10,11,12,12a-hexahydro-(1-hydroxy-2-methoxycarbonyl-3-methylbenzo)[9,10-a]tetraceno[1,12-de][1,3]oxazine-2,6,8,13-tetraone

To a solution of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-imino-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate(87 mg, 0.125 mmol) in THF (1 mL) was added carbonyldiimidazole (24.3mg, 0.15 mmol) at room temperature, and the mixture was stirred undernitrogen for 4 h. The reaction mixture was quenched with a saturatedsolution of ammonium chloride and extracted with chloroform. Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preparative TLC (silica gel,95:5 chloroform/methanol) to afford(8aR,12R,12aS)-8a,12-Dihydroxy-5-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12a-methoxy-8a,9,10,11,12,12a-hexahydro-(1-hydroxy-2-methoxycarbonyl-3-methylbenzo)[9,10-c]tetraceno[1,12-de][1,3]oxazine-2,6,8,13-tetraone(26 mg, 29%) as a red solid: ¹H NMR (500 MHz, CDCl₃) δ 12.15 (s, 1H),8.56 (s, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.56 (s, 1H), 6.30 (s, 1H), 5.16(br s, 1H), 4.96 (br s, 1H), 4.79 (d, J=8.5 Hz, 1H), 4.54 (br s, 1H),3.84 (s, 3H), 3.81 (s, 3H), 3.78-3.72 (m, 3H), 3.61 (s, 3H), 3.60 (dd,J=19.5, 6.5 Hz, 1H), 3.42 (s, 3H), 3.36 (d, J=19.5 Hz, 1H), 3.14 (t,J=9.5 Hz, 1H), 2.45 (d, J=5.0 Hz, 1H), 2.41 (s, 3H), 1.37 (d, J=6.0 Hz,3H); MS (ESI+) m/z 723 (M+H); HPLC 87.3% (AUC), t_(R) 12.05 min.

Example 61 Preparation of (6R,6aS,14aR)-Methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12-((5-(2-hydroxypropyl)furan-3-yl)methyl)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate

Streptomyces sp. AMRI-45379 is a strain isolated from environmentalsamples by AMRI for natural products research deposited in aninternational depositary authority (IDA) collection according to theBudapest Treaty. The strain AMRI-45379 was mailed on Jun. 22, 2010 tothe ATCC Patent Collection by Federal Express Priority Overnight Mailwith Tracking Number 793661147245. The strain AMRI-45379 was received byATCC on Jun. 23, 2010 and assigned ATCC Accession No. PTA-11097. Thisstrain was previously maintained on ISP 2 medium and stored ascryogenically preserved (liquid nitrogen vapor phase) stock solutions inthe appropriate medium (Medium A plus 15% glycerol). ISP 2 medium iscomposed of (per Liter) 4.0 grams Yeast Extract, 10.0 grams MaltExtract, 4.0 grams Dextrose, and, when solidified, 20.0 grams Agar.Medium A is composed of (per Liter) 20.0 grams of soluble starch, 10.0grams of dextrose, 5.0 grams of NZ Amine A, 5.0 grams of yeast extract,and 1.0 grams of calcium carbonate. All media were autoclaved for 30minutes at 16 psi and 122° C. and mixed prior to dispensing into platesor flasks.

Bioconversions were carried out using cells grown according to thefollowing protocol. Vials stored under liquid nitrogen vapor were thawedand approximately 1.0 mL of seed material was inoculated into 250 mLDeLong culture flasks containing 30 mL of Medium A. This culture wasgrown at 28° C., 250 RPM with a 5 cm orbit for 24 hours. The resultingculture was used to inoculate a 250 mL DeLong culture flask containing30 mL ISP 2 at 5% (v/v). This second culture was grown at 28° C., 220RPM with a 5 cm orbit for an additional 24 hours. Cells from thisculture were recovered via centrifugation at 4,000×g for 5 minutes.These cells were subsequently resuspended in an equal volume of MineralSalts Broth lacking a source of nitrogen and supplemented with 10 g/Lsucrose and returned to the same incubation conditions. Mineral SaltsBroth (MSB) was prepared essentially as described by the American TypeCulture Collection (ATCC Medium 1127).

Bioconversions were initiated by the addition of (6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateto the AMRI-45379 suspensions to give a 0.25 mg/mL final concentration.These additions were made from a 25 mg/mL stock solution of(6R,6aS,14aR)-methyl1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatedissolved in dimethylsulfoxide. Bioconversions were allowed to proceedfor 48 hours under the same incubation conditions. At the conclusion ofthe bioconversion, cells were removed via centrifugation and theclarified supernatant was retained.

Supernatant was extracted using High Capacity C18 Alltech SPEcartridges. Roughly, 10 grams of C18 resin were used per liter ofaqueous supernatant. The C18 cartridge was conditioned as permanufacturer's general instructions using acetonitrile for solvationsteps and 10% acetonitrile in distilled water for equilibration steps.Once all supernatant had been loaded onto the C18 resin, the bed waswashed with 4 column volumes of 10% acetonitrile in distilled water.Approximately 2 bed volumes of 20% acetonitrile in distilled water wereeluted from the cartridge under gentle vacuum achieving separation of aleading impurity band from the product band. The product wassubsequently eluted using 1 to 2 bed volumes of 100% acetonitrile. Theacetonitrile was removed under nitrogen. Solids were dissolved indimethylsulfoxide, and the product was isolated via preparatory HPLC.Pure fractions containing (6R,6aS,14aR)-Methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12-((5-(2-hydroxypropyl)furan-3-yl)methyl)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylatewere pooled, the acetonitrile was removed under reduced pressure, andthe remaining aqueous portion was lyophilized. Overall isolatedbiotransformation yields were approximately 20 to 25%.

Preparatory HPLC (Shimadzu) was performed using a Waters Sun Fire™ C18OBD 5 um 30×150 mm column with the mobile phase initially composed of75% of solvent A (water) and 25% of solvent B [acetonitrile]. Elutionwas performed with a linear gradient from 25 to 70% B in 21 minutes at aflow rate of 40 mL/min. UV data were acquired at 254 nm with aninjection volume of 4-5 mL of sample solution.

Analytical HPLC (Shimadzu) was performed at a controlled temperature of40° C. using a Waters Sun Fire™ C18 3.5 um 4.6×100 mm column with themobile phase initially composed of 80% of solvent A (0.1% formic acid inwater) and 20% of solvent B [0.1% (v/v) formic acid in acetonitrile].Elution was performed with an initial isocratic hold for 1 minute,followed by a linear gradient from 20 to 80% B in 12 minutes, and thenisocratic at 80% B for 2 minutes at a flow rate of 1 mL/min. The columnwas re-equilibrated for 3 minutes after programming back to the startingsolvent mixture over 0.5 minute. UV data were acquired using aphotodiode array at 190-370 nm (extraction at 254 nm) with an injectionvolume of 5 μL of sample solution.

LCMS analyses were performed on a PE SCIEX system with a PDA detectorand MS system consisting of API 150 LCMS mass spectrometer.Chromatography was accomplished using a Waters Sun Fire™ C18 3.5 um4.6×100 mm column UV data were acquired using a photodiode array at190-370 nm (extraction at 254 nm) with an injection volume of 5 μL ofsample solution. The mass spectrometer was operated in positive ion modewith spray voltage set at 5400 V. The ion source temperature was set at450° C. The 1.0 mL/min effluent from the HPLC column was directed to TISion source with 13 splitting after UV detection. The delay in signalresponse between the two detectors was less than 0.2 minutes. Theretention time of (6R,6aS,14aR)-Methyl1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-12-((5-(2-hydroxypropyl)furan-3-yl)methyl)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateusing this method is 7.47 minutes. The [M+H]⁺ ion is m/z 838.2.

High resolution mass spectra were gathered on a Waters Premier QT ofmass spectrometer running on the MassLynx software platform and equippedwith an electrospray ionization source. Samples were diluted withH₂O:Acetonitrile (1:1) containing 0.1% formic acid and introduced viainfusion using the onboard syringe pump. The samples were diluted toyield good s/n which occurred at an approximate concentration of 0.01mg/mL The positive electrospray ionization T of mass spectrum acquiredby infusing showed an [M+H]⁺ ion at m/z 838.2933 which was in agreementwith the molecular formula C₄₂H₄₇NO₁₇ (calcd for C₄₂H₄₈NO₁₇: 838.2922,error: 1.3 ppm). Positive electrospray ionization also showed theexpected [M+Na]⁺ ion at m/z 860.2756 which was also in agreement withthe molecular formula C₄₂H₄₇NO₁₇ (calcd for C₄₂H₄₇NO₁₇Na: 860.2742,error: 1.6 ppm).

¹H and ¹³C NMR as well as COSY, HSQC, and HMBC spectra were recordedusing a Bruker DRX 500 NMR spectrometer in CDCl₃ at 500 MHz for ¹H and125 MHz for ¹³C NMR. The spectrum was referenced to the residual solventsignal (δ_(H) 7.24, δ_(C) 77.0 for CDCl₃). Spectra are given in ppm (δ)and coupling constants, J, are reported in Hertz (Table 8).

TABLE 8 ¹H and ¹³C NMR Data for Example 61 in CDCl₃ Position δ_(H) mult.(J in Hz) δ_(c) 1 160.0 1-OH  12.09 s 2 109.9 3 142.9 4   6.53 s 124.44a 142.8 5   3.29 dd (2.5, 20.5) 38.1   3.54 m 6   4.94 bs 62.8 6-OH  4.72 bs 6a 84.3 6a-OCH₃   3.31 s 52.4 7 189.9 7a 117.9 8 163.0 8-OH 15.03 s 8a 119.0 9 187.1 10  5.44 s 97.7 11 166.1 11-NH  6.73 d (8.8)12 73.5 12-OH  4.94 s 12a 151.9 13  7.78 s 113.6 13a 138.6 14 197.9 14a78.9 14a-OH  5.33 s 14b 120.4 15 172.2 15-OCH₃  3.78 s 52.3 16  2.39 s23.9 1′  4.64 d (8.8) 79.4 2′  3.51 m 79.9 2′-OCH₃  3.68 s 62.3 3′  3.68m 75.1 3′-OH 4′  3.04 t (9.1) 82.8 4′-OCH₃  3.52 s 61.1 5′  3.24 dd(6.3, 9.1) 73.1 6′  1.23 d (6.3) 17.9 1″  2.77 d (13.9) 43.6  2.92 d(13.9) 2″ 117.7 3″  5.42 s 109.3 4″ 153.0 5″  2.42 dd (7.6, 14.8) 37.4 2.53 dd (4.1, 14.8) 6″  3.84 m 66.4 6″-OH 7″  1.06 d (6.0) 22.9 8″ 6.66 s 140.1

Example 62 Antibacterial Activity

NCCLS standards for antimicrobial susceptibility testing using thedilution method were followed. See: Performance Standards forAntimicrobial Susceptibility Testing; Fourteenth InformationalSupplement. NCCLS Document M100-S14 (ISBN 1-56238-516-X), 2004. NCCLS,940 West Valley Road, Suite 1400, Wayne, Pa. 19087-1898 USA, 2004;Methods for Dilution Antimicrobial Susceptibility Tests for Bacteriathat Grow Aerobically; Approved Standard Sixth Edition. NCCLS documentM7-A6 (IBSBN 1-56238-486-4), NCCLS, 940 West Valley Road, Suite 1400,Wayne, Pa. 19087-1898 USA, 2003, which are hereby incorporated byreference in their entirety.

The results are set forth in Table 9, below:

TABLE 9 Antibacterial Activity MRSA 43300 Example # MIC, μg/mL  2  0.008 4  0.06-0.12  5^(a)  2  6  0.12  7  0.12  8  1  9^(a) 32 10^(a) 32 11 0.12-0.25 12  0.25-1 13 32 16^(a) 16 17^(a) 32 18^(a)  2 19^(a)  2 20 2 21  1 22^(a)  1 23^(a)  4 24^(a) 32 25^(a)  2-4 26^(a)  0.5 27^(a)  828^(a)  0.5 30^(a)  0.12-0.5 31^(a)  2 33  1-2 34  0.008-0.016 36  0.1237^(a)  0.25 38  1 39  2 40  1 40  2 42  2-4 44  1-2 46  1 47  1-2 48  149  0.06 50  0.25 51  8 52  0.12-0.25 53  0.12 54  2 55 32 55 16 56  856 16 57 16 57  4-8 58  8-16 59 32 60  0.12-0.5 61  0.06 ^(a)Tested as amixture of diastereomers.

Example 63 Testing for Antibacterial Activities (In Vitro)

A compound having the formula:

was tested for antibacterial activity, as follows:

NCCLS standards for antimicrobial susceptibility testing using thedilution method were followed. See: Performance Standards forAntimicrobial Susceptibility Testing; Fourteenth InformationalSupplement. NCCLS Document M100-S14 (ISBN 1-56238-516-X), 2004. NCCLS,940 West Valley Road, Suite 1400, Wayne, Pa. 19087-1898 USA, 2004;Methods for Dilution Antimicrobial Susceptibility Tests for Bacteriathat Grow Aerobically; Approved Standard Sixth Edition. NCCLS documentM7-A6 (IBSBN 1-56238-486-4), NCCLS, 940 West Valley Road, Suite 1400,Wayne, Pa. 19087-1898 USA, 2003, which are hereby incorporated byreference in their entirety. The results are shown in Table 10, below:

TABLE 10 Organism & Strain # Gram +/− Phenotype Vancomycin Cmpd 12Linezolid Meropenem S. aureus (ATCC 6538) + MSSA 0.5 0.008 0.5 S. aureus(ATCC 29213) + MSSA 1 ≦0.06 4 0.12 S. aureus 1137 + MRSA 1 ≦0.06 4 >4 S.aureus (ATCC 43300) + MRSA 2 0.008 1 S. aureus 2012 + VISA 8 ≦0.06 1 >4S. aureus 2018 + VISA 8 ≦0.06 S. aureus 1725 + LRSA 1 ≦0.06 4 0.25 S.aureus 1651 + LRSA 1 ≦0.06 S. aureus 2144 + CA, USA 1 ≦0.06 300 StrainS. epidermidis 1597 + MSSE 2 ≦0.06 S. epidermidis 1452 + MRSE 2 ≦0.06 S.saprophyticus 495 + 1 ≦0.06 E. faecalis 846 + VRE >64 ≦0.06 E. faecium700221 + VRE >64 0.06 1 S. pneumoniae 975 + PSSP 0.5 ≦0.06 1 0.015 S.pneumoniae 940 + PRSP 0.25 ≦0.06 0.5 1 S. pneumoniae 376 + Quin-R 0.5≦0.06 1 0.015 S. pneumoniae 933 + MDR 0.5 ≦0.06 S. pyogenes 723 + 0.5≦0.06 S. agalactiae 2033 + 0.5 ≦0.06 H. influenzae 1742 − ampR >64 4 80.06 H. parainfluenzae − 64 8 16 0.03 2319 (ATCC 7901) E. coli 102 − QCstrain >64 32 >64 0.03 (ATCC 25922) E. coli 2269 − ESBL-producer >6432 >64 0.03 K. pneumoniae 2239 − >64 64 >64 0.06 K. pneumoniae 2262ampC, MDR >64 64 >64 >4 M. catarrhalis 557 − >64 0.12 8 ≦0.04 S.marcescens 1635 − >64 64 >64 0.12 P. aeruginosa ) − >64 32 >64 (ATCC27853

The present invention is not limited to the compounds found in the aboveexamples, and many other compounds falling within the scope of theinvention may also be prepared using the procedures set forth in theabove synthetic schemes. The preparation of additional compounds offormula I using these methods will be apparent to one of ordinary skillin the chemical arts.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

What is claimed:
 1. A method for making a product compound having theformula:

said method comprising: fermenting a culture medium comprisingStreptomyces strain AMRI-7957 (ATCC Accession No. PTA-11098) underconditions effective to produce a fermentation broth comprising theproduct compound, and isolating the product compound.
 2. The methodaccording to claim 1, wherein fermenting comprises: culturingStreptomyces strain AMRI-7957 (ATCC Accession No. PTA-11098), andinoculating the culture into a fermentor.
 3. The method according toclaim 1, wherein isolating comprises: separating the fermentation brothinto a biomass fraction and a supernatant fraction.
 4. The methodaccording to claim 3, wherein isolating comprises: extracting theproduct compound from the biomass fraction.
 5. The method according toclaim 3, wherein isolating comprises: extracting the product compoundfrom the supernatant fraction.
 6. A method of making a product compoundof formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate compound having the structure

under conditions effective to form the product compound.
 7. The methodaccording to claim 6, wherein treating comprises reacting the firstintermediate with R¹Z¹, wherein Z¹ is a halide.
 8. A method of making aproduct compound of formula I

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate compound having the structure:

under conditions effective to form the product compound.
 9. The methodaccording to claim 8, wherein treating comprises reacting the firstintermediate with R²Z², wherein Z² is a halide or H.
 10. A method ofmaking a product compound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate compound having the structure:

under conditions effective to form the product compound.
 11. The methodaccording to claim 10, wherein treating comprises reacting the firstintermediate compound with N—R³-succinimide.
 12. The method according toclaim 10, wherein R³ is NO₂ and treating comprises reacting the firstintermediate with a nitration agent.
 13. The method according to claim12, wherein the nitration agent is zirconyl(IV) nitrate hydrate.
 14. Themethod according to claim 12 further comprising: reacting the productcompound with a reducing agent.
 15. A method of making a productcompound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 16. The methodaccording to claim 15, wherein R⁴ is ═NR¹⁴ and treating comprisesreacting the first intermediate with NH₂R¹⁴.
 17. A method of making aproduct compound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 18. The methodaccording to claim 17, wherein treating comprises reacting the firstintermediate compound with R⁵Z¹, wherein Z¹ is a halide.
 19. A method ofmaking a product compound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of (CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —N¹²R¹³, (CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, (CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 20. The methodaccording to claim 19, wherein X is N and treating comprises reactingthe first intermediate with NH₂R⁶.
 21. The method according to claim 19further comprising: reacting the product compound with a coupling agentsuch that R⁵ and R⁶ combine to form a heterocycle group containing from1 to 5 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur and optionally substituted 1 to 3 times withhalogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy. 22.The method according to claim 21, wherein the coupling agent iscarbonyldiimidazole.
 23. A method of making a product compound offormula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure

under conditions effective to form the product compound.
 24. The methodaccording to claim 23, wherein treating comprises reacting the firstintermediate compound with N—R⁷-succinimide.
 25. The method according toclaim 23, wherein R⁷ is —NO₂ and treating comprises reacting the firstintermediate with a nitration agent.
 26. The method according to claim25, wherein the nitration agent is zirconyl(IV) nitrate hydrate.
 27. Themethod according to claim 25 further comprising: reacting the productcompound with a reducing agent.
 28. A method of making a productcompound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 29. The methodaccording to claim 28, wherein treating comprises reacting the firstintermediate with R⁸-M-L, wherein M is a metal and L is a halide. 30.The method according to claim 28, wherein treating comprises reactingthe first intermediate with R⁹-M-L, wherein M is a metal and L is ahalide.
 31. A method of making a product compound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 32. The methodaccording to claim 31, wherein Y is N and treating comprises reactingthe first intermediate with NH₂R¹⁰.
 33. A method of making a productcompound of formula I:

wherein: the carbohydrate anomeric carbon designated * is in the R or Sconfiguration; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³,arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety,an ═NR¹⁴ moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, anamino acid group, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂,—OR¹², or —NR¹²R¹³; R² is selected from the group consisting of H,—OR¹², —NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R³ is selected from the group consisting of H, halogen, —OR¹²,—NR¹²R¹³, —NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹²,—CN, —NO₂, —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁴ is selected from the groupconsisting of H, halogen, —OR¹², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, —(CH₂)_(n)OC(O)NR¹²R¹³, phenyl, benzyl, ═NOR¹⁴,═NR¹⁴, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from1 to 3 substituents independently selected at each occurrence thereoffrom C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, an amino acid group,and phenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁵ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, benzyl, a benzyl ethermoiety, a carbamate moiety, an ═NR¹⁴ moiety, and a carbonate moiety,wherein each of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R⁶ is optionally present and, if present, is selected from thegroup consisting of H, —OR¹², —NR¹²R¹³, —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, benzyl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl, and benzylis optionally substituted 1 to 3 times with halogen, cyano, —NO₂,—NR¹²R¹³, —OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an aminoacid group; or R⁵ and R⁶ can combine to form a heterocycle groupcontaining from 1 to 5 heteroatoms selected from the group consisting ofoxygen, nitrogen, and sulfur and optionally substituted 1 to 3 timeswith halogen, oxo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;R⁷ is selected from the group consisting of H, halogen, —OR¹², —NR¹²R¹³,—NR¹²C(O)R¹³, —NR¹²C(O)₂R¹³, —NR¹²C(O)NR¹²R¹³, —S(O)_(q)R¹², —CN, —NO₂,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, abenzyl ether moiety, a carbamate moiety, an ═NR¹⁴ moiety, and acarbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹², —NR¹²R¹³, an amino acid group, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹², or —NR¹²R¹³; R⁸ and R⁹ are each independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —OR¹², phenyl, benzyl, a benzyl ether moiety, acarbamate moiety, and a carbonate moiety, wherein each of C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³, phenyl, and benzyl isoptionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R⁸ and R⁹ can combine to form an oxo, thio, imine, or an═NR¹⁴ moiety; R¹⁰ is optionally present and, if present, is selectedfrom the group consisting of H, —OR¹², —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, acarbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR¹⁴moiety, and a carbonate moiety, wherein each of —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)C(O)NR¹²R¹³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and benzyl isoptionally substituted 1 to 3 times with halogen, cyano, —NO₂, —NR¹²R¹³,—OR¹², C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acidgroup; R¹¹ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, whereineach of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl,and benzyl is optionally substituted 1 to 3 times with halogen, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, or an amino acid group; R¹²and R¹³ are each independently selected from the group consisting of H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹⁶R¹⁷,—(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷, —(CH₂)_(n)NC(O)NR¹⁶R¹⁷,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)NR¹⁶R¹⁷,—(CH₂)_(n)C(O)R¹¹, —(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹,—(CH₂)_(n)C(O)NR¹⁶R¹⁷, —(CH₂)_(n)OC(O)NR¹⁶R¹⁷, —(CH₂)_(n)NR¹⁶C(O)OR¹⁷,—(CH₂)_(n)NC(O)NR¹⁶R¹⁷, aryl, heteroaryl, arylalkyl, and heteroarylalkylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, OH, C₁-C₄ alkoxy, an amino acid group, or[NR¹¹C(O)(CH₂)_(n)]_(m)NR¹⁶R¹⁷, which is optionally substituted 1 to 3times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy, aryl alkyl, wherein the C₁-C₄ alkyl and the aryl alkylsubstituents are optionally substituted 1 to 3 times with halogen,alkyl, OH, NH₂, —CO₂H, —C(O)NH₂, —NHC(O)NH₂, —NHC(NH)NH₂, imidazole,pyrolidine, SMe, SH, or SeH; or R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a five- to seven-memberedheterocyclic ring, which may be saturated or unsaturated and comprisesfrom 1 to 2 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and is optionally substituted from 1 to 4 times witha substituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; R¹⁴ is selected from the group consisting of H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —S(O)_(q)R¹², —(CH₂)_(n)NR¹²R¹³, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —(CH₂)_(n)C(O)R¹¹,—(CH₂)_(n)OC(O)R¹¹, —(CH₂)_(n)C(O)₂R¹¹, —(CH₂)_(n)C(O)NR¹²R¹³,—(CH₂)_(n)OC(O)NR¹²R¹³, —(CH₂)_(n)NR¹¹C(O)OR¹², —(CH₂)_(n)NC(O)NR¹²R¹³,aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹², —NR¹²R¹³, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —NO₂, —OR¹², —NR¹²R¹³, or anamino acid group; R¹⁵ is H, C₁-C₄ alkyl, arylalkyl, heteroarylalkylC₁-C₄ haloalkyl, or phenyl, wherein each of C₁-C₄ alkyl, arylalkyl,heteroarylalkyl C₁-C₄ haloalkyl, and phenyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, or an amino acid group; R¹⁶ and R¹⁷ are each independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, —C(O)OR¹⁵, phenyl, or benzyl, wherein each ofC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, and benzylis optionally substituted from 1 to 3 times with a substituent selectedindependently at each occurrence thereof from the group consisting ofhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and an aminoacid group; or R¹⁶ and R¹⁷ are taken together with the nitrogen to whichthey are attached to form a five- to seven-membered heterocyclic ring,which may be saturated or unsaturated and comprises from 1 to 2heteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and is optionally substituted from 1 to 4 times with asubstituent selected independently at each occurrence thereof from thegroup consisting of halogen, cyano, oxo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,and C₁-C₄ alkoxy; X is O or N; Y is O or N; m is 0, 1, 2, or 3; n is 0to 5; q is 0, 1, or 2; and

represents an optional double bond; said method comprising: treating afirst intermediate having the structure:

under conditions effective to form the product compound.
 34. The methodaccording to claim 33, wherein treating comprises reacting the firstintermediate with an imidate having a formula:


35. The method according to claim 34, wherein the imidate is